@article{akinsipe_mohamedelhassan_akinpelu_pondugula_mistriotis_avila_suryawanshi_2024, title={Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics}, volume={15}, ISSN={1664-3224}, url={http://dx.doi.org/10.3389/fimmu.2024.1302587}, DOI={10.3389/fimmu.2024.1302587}, abstractNote={The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.}, journal={Frontiers in Immunology}, publisher={Frontiers Media SA}, author={Akinsipe, Tosin and Mohamedelhassan, Rania and Akinpelu, Ayuba and Pondugula, Satyanarayana R. and Mistriotis, Panagiotis and Avila, L. Adriana and Suryawanshi, Amol}, year={2024}, month={Mar} }
 @article{alrbyawi_annaji_fasina_palakurthi_boddu_hassan_tiwari_suryawanshi_babu_2024, title={Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A}, volume={25}, ISSN={1530-9932}, url={http://dx.doi.org/10.1208/s12249-024-02738-5}, DOI={10.1208/s12249-024-02738-5}, abstractNote={Abstract Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) ( P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.}, number={2}, journal={AAPS PharmSciTech}, publisher={Springer Science and Business Media LLC}, author={Alrbyawi, Hamad and Annaji, Manjusha and Fasina, Oladiran and Palakurthi, Srinath and Boddu, Sai H. S. and Hassan, Nageeb and Tiwari, Amit K. and Suryawanshi, Amol and Babu, R. Jayachandra}, year={2024}, month={Feb} }
 @article{antony_kinha_nowinska_rouse_suryawanshi_2024, title={The immunobiology of corneal HSV-1 infection and herpetic stromal keratitis}, url={https://doi.org/10.1128/cmr.00006-24}, DOI={10.1128/cmr.00006-24}, abstractNote={SUMMARY Human alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains.}, journal={Clinical Microbiology Reviews}, author={Antony, F. and Kinha, D. and Nowinska, A. and Rouse, B.T. and Suryawanshi, A.}, editor={Forrest, Graeme N.Editor}, year={2024} }
 @article{antony_pundkar_sandey_mishra_suryawanshi_2023, title={Role of IL-27 in HSV-1–Induced Herpetic Stromal Keratitis}, volume={211}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.2200420}, DOI={10.4049/jimmunol.2200420}, abstractNote={Herpetic stromal keratitis (HSK) is a painful and vision-impairing disease caused by recurrent HSV-1 infection of the cornea. The virus replication in the corneal epithelium and associated inflammation play a dominant role in HSK progression. Current HSK treatments targeting inflammation or virus replication are partially effective and promote HSV-1 latency, and long-term use can cause side effects. Thus, understanding molecular and cellular events that control HSV-1 replication and inflammation is crucial for developing novel HSK therapies. In this study, we report that ocular HSV-1 infection induces the expression of IL-27, a pleiotropic immunoregulatory cytokine. Our data indicate that HSV-1 infection stimulates IL-27 production by macrophages. Using a primary corneal HSV-1 infection mouse model and IL-27 receptor knockout mice, we show that IL-27 plays a critical role in controlling HSV-1 shedding from the cornea, the optimum induction of effector CD4+ T cell responses, and limiting HSK progression. Using in vitro bone marrow-derived macrophages, we show that IL-27 plays an antiviral role by regulating macrophage-mediated HSV-1 killing, IFN-β production, and IFN-stimulated gene expression after HSV-1 infection. Furthermore, we report that IL-27 is critical for macrophage survival, Ag uptake, and the expression of costimulatory molecules involved in the optimum induction of effector T cell responses. Our results indicate that IL-27 promotes endogenous antiviral and anti-inflammatory responses and represents a promising target for suppressing HSK progression.}, number={3}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Antony, Ferrin and Pundkar, Chetan and Sandey, Maninder and Mishra, Amarjit and Suryawanshi, Amol}, year={2023}, month={Jun}, pages={474–485} }
 @article{ren_antony_rouse_suryawanshi_2023, title={Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis}, volume={12}, ISSN={2076-0817}, url={http://dx.doi.org/10.3390/pathogens12030437}, DOI={10.3390/pathogens12030437}, abstractNote={Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host's life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host's innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/β) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.}, number={3}, journal={Pathogens}, publisher={MDPI AG}, author={Ren, Jiayi and Antony, Ferrin and Rouse, Barry T. and Suryawanshi, Amol}, year={2023}, month={Mar}, pages={437} }
 @article{pundkar_antony_kang_mishra_babu_chen_li_suryawanshi_2023, title={Targeting β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity}, volume={9}, ISSN={2405-8440}, url={http://dx.doi.org/10.1016/j.heliyon.2023.e16688}, DOI={10.1016/j.heliyon.2023.e16688}, abstractNote={The aberrant activation of Wnt/β-catenin signaling in tumor cells and immune cells in the tumor microenvironment (TME) promotes malignant transformation, metastasis, immune evasion, and resistance to cancer treatments. The increased Wnt ligand expression in TME activates β-catenin signaling in antigen (Ag)-presenting cells (APCs) and regulates anti-tumor immunity. Previously, we showed that activation of Wnt/β-catenin signaling in dendritic cells (DCs) promotes induction of regulatory T cell responses over anti-tumor CD4+ and CD8+ effector T cell responses and promotes tumor progression. In addition to DCs, tumor-associated macrophages (TAMs) also serve as APCs and regulate anti-tumor immunity. However, the role of β-catenin activation and its effect on TAM immunogenicity in TME is largely undefined. In this study, we investigated whether inhibiting β-catenin in TME-conditioned macrophages promotes immunogenicity. Using nanoparticle formulation of XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we performed in vitro macrophage co-culture assays with melanoma cells (MC) or melanoma cell supernatants (MCS) to investigate the effect on macrophage immunogenicity. We show that XAV-Np-treatment of macrophages conditioned with MC or MCS significantly upregulates the cell surface expression of CD80 and CD86 and suppresses the expression of PD-L1 and CD206 compared to MC or MCS-conditioned macrophages treated with control nanoparticle (Con-Np). Further, XAV-Np-treated macrophages conditioned with MC or MCS significantly increased IL-6 and TNF-α production, with reduced IL-10 production compared to Con-Np-treated macrophages. Moreover, the co-culture of MC and XAV-Np-treated macrophages with T cells resulted in increased CD8+ T cell proliferation compared to Con-Np-treated macrophages. These data suggest that targeted β-catenin inhibition in TAMs represents a promising therapeutic approach to promote anti-tumor immunity.}, number={6}, journal={Heliyon}, publisher={Elsevier BV}, author={Pundkar, Chetan and Antony, Ferrin and Kang, Xuejia and Mishra, Amarjit and Babu, R. Jayachandra and Chen, Pengyu and Li, Feng and Suryawanshi, Amol}, year={2023}, month={Jun}, pages={e16688} }
 @article{antony_kang_pundkar_wang_mishra_chen_babu_suryawanshi_2023, title={Targeting β-catenin using XAV939 nanoparticle promotes immunogenic cell death and suppresses conjunctival melanoma progression}, volume={640}, ISSN={0378-5173}, url={http://dx.doi.org/10.1016/j.ijpharm.2023.123043}, DOI={10.1016/j.ijpharm.2023.123043}, abstractNote={Many tumors dysregulate Wnt/β-catenin pathway to promote stem-cell-like phenotype, tumorigenesis, immunosuppression, and resistance to targeted cancer immunotherapies. Therefore, targeting this pathway is a promising therapeutic approach to suppress tumor progression and elicit robust anti-tumor immunity. In this study, using a nanoparticle formulation for XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we investigated the effect of β-catenin inhibition on melanoma cell viability, migration, and tumor progression using a mouse model of conjunctival melanoma. XAV-Nps were uniform and displayed near-spherical morphology with size stability for upto 5 days. We show that XAV-Np treatment of mouse melanoma cells significantly suppresses cell viability, tumor cell migration, and tumor spheroid formation compared to control nanoparticle (Con-Np) or free XAV939-treated groups. Further, we demonstrate that XAV-Np promotes immunogenic cell death (ICD) of tumor cells with a significant extracellular release or expression of ICD molecules, including high mobility group box 1 protein (HMGB1), calreticulin (CRT), and adenosine triphosphate (ATP). Finally, we show that local intra-tumoral delivery of XAV-Nps during conjunctival melanoma progression significantly suppresses tumor size and conjunctival melanoma progression compared to Con-Nps-treated animals. Collectively, our data suggest that selective inhibition of β-catenin in tumor cells using nanoparticle-based targeted delivery represents a novel approach to suppress tumor progression through increased tumor cell ICD.}, journal={International Journal of Pharmaceutics}, publisher={Elsevier BV}, author={Antony, Ferrin and Kang, Xuejia and Pundkar, Chetan and Wang, Chuanyu and Mishra, Amarjit and Chen, Pengyu and Babu, R. Jayachandra and Suryawanshi, Amol}, year={2023}, month={Jun}, pages={123043} }
 @article{ruiz_haynes_marable_pundkar_nance_bedi_agarwal_suryawanshi_mishra_smith_et al._2022, title={Development of OX40 agonists for canine cancer immunotherapy}, volume={25}, ISSN={2589-0042}, url={http://dx.doi.org/10.1016/j.isci.2022.105158}, DOI={10.1016/j.isci.2022.105158}, abstractNote={Recent breakthroughs in cancer immunotherapy have provided unprecedented clinical benefits to human cancer patients. Cancer is also one of the most common causes of death in pet dogs. Thus, canine-specific immune therapies targeting similar signaling pathways can provide better treatment options for canine cancer patients. Here, we describe the development and characterization of two canine-specific anti-OX40 agonists to activate OX40 signaling. We show that canine OX40, like human OX40, is not expressed on resting T cells, and its expression is markedly increased on canine CD4 T cells and Tregs after stimulation with concanavalin A (Con-A). cOX40 is also expressed on tumor-infiltrating lymphocytes (TILs) in canine osteosarcoma patients. The canine-specific OX40 agonists strongly activates cPBMCs by increasing IFN-γ expression and do not require Fc receptor-mediated cross-linking for OX40 agonism. Together, these results suggest that cFcOX40L proteins are potent OX40 agonists and have the potential to enhance antitumor immunity in canine cancer patients.}, number={10}, journal={iScience}, publisher={Elsevier BV}, author={Ruiz, Damien and Haynes, Chloe and Marable, Jonathan and Pundkar, Chetan and Nance, Rebecca L. and Bedi, Deepa and Agarwal, Payal and Suryawanshi, Amol S. and Mishra, Amarjit and Smith, Bruce F. and et al.}, year={2022}, month={Oct}, pages={105158} }
 @article{das_ahmad_suryawanshi_kumar_2022, title={Innate immunity dysregulation in aging eye and therapeutic interventions}, volume={82}, ISSN={1568-1637}, url={http://dx.doi.org/10.1016/j.arr.2022.101768}, DOI={10.1016/j.arr.2022.101768}, abstractNote={The prevalence of eye diseases increases considerably with age, resulting in significant vision impairment. Although the pathobiology of age-related eye diseases has been studied extensively, the contribution of immune-related changes due to aging remains elusive. In the eye, tissue-resident cells and infiltrating immune cells regulate innate responses during injury or infection. But due to aging, these cells lose their protective functions and acquire pathological phenotypes. Thus, dysregulated ocular innate immunity in the elderly increases the susceptibility and severity of eye diseases. Herein, we emphasize the impact of aging on the ocular innate immune system in the pathogenesis of infectious and non-infectious eye diseases. We discuss the role of age-related alterations in cellular metabolism, epigenetics, and cellular senescence as mechanisms underlying altered innate immune functions. Finally, we describe approaches to restore protective innate immune functions in the aging eye. Overall, the review summarizes our current understanding of innate immune functions in eye diseases and their dysregulation during aging.}, journal={Ageing Research Reviews}, publisher={Elsevier BV}, author={Das, Susmita and Ahmad, Zeeshan and Suryawanshi, Amol and Kumar, Ashok}, year={2022}, month={Dec}, pages={101768} }
 @article{jaiswal_yadav_makhija_mazumder_mitra_suryawanshi_sandey_mishra_2022, title={Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation}, volume={15}, ISSN={1933-0219}, url={http://dx.doi.org/10.1038/s41385-021-00462-y}, DOI={10.1038/s41385-021-00462-y}, abstractNote={Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, the role of the Irg1/itaconate pathway in dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are the primary antigen-presenting cells in allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1−/− mice displayed increases in eosinophilic airway inflammation, mucous cell metaplasia, and Th2 cytokine production with a mechanism involving impaired mite antigen presentations by DC. Adoptive transfer of HDM-pulsed DC from Irg1-deficient mice into naïve WT mice induced a similar phenotype of elevated type 2 airway inflammation and allergic sensitization. Untargeted metabolite analysis of HDM-pulsed DC revealed itaconate as one of the most abundant polar metabolites that potentially suppress mitochondrial oxidative damage. Furthermore, the immunomodulatory effect of itaconate was translated in vivo, where intranasal administration of 4-octyl itaconate 4-OI following antigen priming attenuated the manifestations of HDM-induced airway disease and Th2 immune response. Taken together, these data demonstrated for the first time a direct regulatory role of the Irg1/itaconate pathway in DC for the development of type 2 airway inflammation and suggest a possible therapeutic target in modulating allergic asthma.}, number={2}, journal={Mucosal Immunology}, publisher={Elsevier BV}, author={Jaiswal, Anil Kumar and Yadav, Jyoti and Makhija, Sangeet and Mazumder, Suman and Mitra, Amit Kumar and Suryawanshi, Amol and Sandey, Maninder and Mishra, Amarjit}, year={2022}, month={Feb}, pages={301–313} }
 @article{jaiswal_yadav_makhija_sandey_suryawanshi_mitra_mishra_2022, title={Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging}, volume={322}, ISSN={1040-0605 1522-1504}, url={http://dx.doi.org/10.1152/ajplung.00315.2021}, DOI={10.1152/ajplung.00315.2021}, abstractNote={Asthma and its heterogeneity change with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adults with asthma. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we used a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adult (20–22 wk old) and aged (80–82 wk old) mice. Our result indicates an age-dependent increase in airway hyperresponsiveness (AHR), mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNA-Seq experiments of the aged lung revealed short palate, lung, and nasal epithelial clone 1 (SPLUNC1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.}, number={1}, journal={American Journal of Physiology-Lung Cellular and Molecular Physiology}, publisher={American Physiological Society}, author={Jaiswal, Anil Kumar and Yadav, Jyoti and Makhija, Sangeet and Sandey, Maninder and Suryawanshi, Amol and Mitra, Amit Kumar and Mishra, Amarjit}, year={2022}, month={Jan}, pages={L102–L115} }
 @article{antony_pundkar_sandey_jaiswal_mishra_kumar_channappanavar_suryawanshi_2021, title={IFN-λ Regulates Neutrophil Biology to Suppress Inflammation in Herpes Simplex Virus-1–Induced Corneal Immunopathology}, volume={206}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.2000979}, DOI={10.4049/jimmunol.2000979}, abstractNote={Abstract HSV-1 infection of the cornea causes a severe immunoinflammatory and vision-impairing condition called herpetic stromal keratitis (SK). The virus replication in corneal epithelium followed by neutrophil- and CD4+ T cell–mediated inflammation plays a dominant role in SK. Although previous studies demonstrate critical functions of type I IFNs (IFN-α/β) in HSV-1 infection, the role of recently discovered IFN-λ (type III IFN), specifically at the corneal mucosa, is poorly defined. Our study using a mouse model of SK pathogenesis shows that HSV-1 infection induces a robust IFN-λ response compared with type I IFN production at the corneal mucosal surface. However, the normal progression of SK indicates that the endogenous IFN responses are insufficient to suppress HSV-1–induced corneal pathology. Therefore, we examined the therapeutic efficacy of exogenous rIFN-λ during SK progression. Our results show that rIFN-λ therapy suppressed inflammatory cell infiltration in the cornea and significantly reduced the SK pathologic condition. Early rIFN-λ treatment significantly reduced neutrophil and macrophage infiltration, and IL-6, IL-1β, and CXCL-1 production in the cornea. Notably, the virucidal capacity of neutrophils and macrophages measured by reactive oxygen species generation was not affected. Similarly, ex vivo rIFN-λ treatment of HSV-1–stimulated bone marrow–derived neutrophils significantly promoted IFN-stimulated genes without affecting reactive oxygen species production. Collectively, our data demonstrate that exogenous topical rIFN-λ treatment during the development and progression of SK could represent a novel therapeutic approach to control HSV-1–induced inflammation and associated vision impairment.}, number={8}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Antony, Ferrin and Pundkar, Chetan and Sandey, Maninder and Jaiswal, Anil K. and Mishra, Amarjit and Kumar, Ashok and Channappanavar, Rudragouda and Suryawanshi, Amol}, year={2021}, month={Apr}, pages={1866–1877} }
 @article{marable_ruiz_jaiswal_bhattacharya_pantazes_agarwal_suryawanshi_bedi_mishra_smith_et al._2021, title={Nanobody-based CTLA4 inhibitors for immune checkpoint blockade therapy of canine cancer patients}, volume={11}, ISSN={2045-2322}, url={http://dx.doi.org/10.1038/s41598-021-00325-3}, DOI={10.1038/s41598-021-00325-3}, abstractNote={Cancer is the leading cause of death in the geriatric dog population. Currently, the use of immune checkpoint inhibitors (ICIs) such as anti-CTLA4 antibodies has markedly improved the prognosis of several cancers in their advanced stages. However, ICIs targeting CTLA4 blockade to treat canine cancer patients are yet to define. In this study, we sought to develop, characterize and assess whether chimeric heavy chain only antibodies (cHcAbs) against CTLA4 are viable therapeutic candidates for the treatment of canine cancers. Anti-CTLA4 nanobodies (Nbs) were identified from a yeast nanobody (Nb) library using magnetic-assisted cell sorting (MACS) and flow cytometry. cHcAbs were engineered by genetically fusing the DNA sequences coding for anti-CTLA4 Nbs with the Fc domain of the subclass B of canine IgG. Recombinant cHcAbs were purified from ExpiCHO-S cells. Stable cell lines expressing canine CTLA4 and FcγRI were used to elucidate the binding ability and specificity of cHcAbs. PBMCs isolated from healthy dogs were used to evaluate the ability of cHcAbs to activate canine PBMCs (cPBMCs). Novel Nbs were identified using the extracellular domain of canine CTLA4 protein to screen a fully synthetic yeast nanobody library. Purified Nbs bind specifically to natïve canine CTLA4. We report that chimeric HcAbs, which were engineered by fusing the anti-CTLA4 Nbs and Fc region of subclass B of canine IgG, were half the size of a conventional mAb and formed dimers. The chimeric HcAbs specifically binds both with canine CTLA4 and Fcγ receptors. As the binding of Nbs overlapped with the MYPPPY motif of canine CTLA4, these Nbs were expected to sterically disrupt the interaction of canine CTLA4 to B-7s. Like their human counterpart, canine CTLA4 was expressed on helper T cells and a small subset of cytotoxic T cells. Canine Tregs also constitutively expressed CTLA4, and stimulation with PMA/Ionomycin dramatically increased expression of CTLA4 on the cell surface. Stimulation of cPBMCs in the presence of agonistic anti-CD3 Ab and cHcAb6 significantly increased the expression of IFN-γ as compared to the isotype control. This study identifies a novel nanobody-based CTLA4 inhibitor for the treatment of canine cancer patients.}, number={1}, journal={Scientific Reports}, publisher={Springer Science and Business Media LLC}, author={Marable, Jonathan and Ruiz, Damien and Jaiswal, Anil K. and Bhattacharya, Ritankar and Pantazes, Robert and Agarwal, Payal and Suryawanshi, Amol S. and Bedi, Deepa and Mishra, Amarjit and Smith, Bruce F. and et al.}, year={2021}, month={Oct} }
 @article{kang_cai_wang_wang_chen_yang_suryawanshi_zhou_chen_li_2021, title={Near-infrared light triggered activation of pro-drug combination cancer therapy and induction of immunogenic cell death}, volume={607}, ISSN={0378-5173}, url={http://dx.doi.org/10.1016/j.ijpharm.2021.120972}, DOI={10.1016/j.ijpharm.2021.120972}, abstractNote={Disulfiram copper complex [Cu(DDC)2] nanoparticles have been explored as promising anticancer agents but with concerns of toxic side effects. To improve tumor specificity and enhance anticancer efficacy, we developed a novel [copper sulfide nanoparticle (CuS NP) + disulfiram prodrug (DQ) micelle + near-infrared (NIR) laser] (CDL) combination therapy. DQ, a reactive oxygen species (ROS)-responsive prodrug, can be selectively activated at the tumor site with elevated ROS to release DDC and form Cu(DDC)2 in situ. The CuS NP + NIR laser treatment can effectively increase the intra-tumor ROS levels and efficiently activate the DQ prodrug. The CDL therapy kills cancer cells through multiple mechanisms, including ROS amplification cascade and Cu(DDC)2 chemotherapy. NIR light-triggered tumor-specific "nontoxic-to-toxic" transition can significantly improve the specificity of anticancer effects and reduce systemic toxicity. Also, CDL therapy can effectively induce immunogenic cell death (ICD) and has the potential of eliciting antitumor immunity.}, journal={International Journal of Pharmaceutics}, publisher={Elsevier BV}, author={Kang, Xuejia and Cai, Yuxin and Wang, Qi and Wang, Chuanyu and Chen, Wu and Yang, Wen and Suryawanshi, Amol and Zhou, Gang and Chen, Pengyu and Li, Feng}, year={2021}, month={Sep}, pages={120972} }
 @article{jaiswal_makhija_stahr_sandey_suryawanshi_saxena_dagur_mccoy_levine_mishra_2020, title={Dendritic Cell-Restricted Progenitors Contribute to Obesity-Associated Airway Inflammation via Adam17-p38 MAPK-Dependent Pathway}, volume={11}, ISSN={1664-3224}, url={http://dx.doi.org/10.3389/fimmu.2020.00363}, DOI={10.3389/fimmu.2020.00363}, abstractNote={Proliferation of dendritic cell (DC) - restricted progenitor cells in bone marrow compartment is tightly regulated at steady state and responds to multiple tissue-specific triggers during disturbed homeostasis such as obesity. DCs in the lung stem from a rapidly dividing DC-restricted progenitor cells and are effective at generating adaptive immune responses in allergic airway inflammation. Precisely, how DC-restricted progenitor expansion and differentiation are influenced by airway inflammation to maintain constant supply of myeloid DCs is poorly understood. Here we show that a high fat diet (HFD) induces oxidative stress and accelerates the expansion of DC- restricted progenitor cells in bone marrow and correlates with persistent induction of p38 mitogen activated protein kinase (MAPK), which is blocked with a selective p38α/β MAPK inhibitor. Mice fed a HFD and sensitized to inhaled allergen house dust mite (HDM) led to alterations of DC- restricted progenitor cells that were characterized by increased expansion and seeding of lung DCs in airway inflammation. Mechanistically, we establish that the expansion induced by HFD dysregulates the expression of a disintegrin and metallopeptidase domain 17 (Adam17) and is required for p38 MAPK activation in DC-restricted progenitors. These results demonstrates that obesity produces persistent changes in DC precursors and that elevation of Adam17 expression is tightly coupled to p38 MAPK and is a key driver of proliferation. Altogether, these data provide phenotypic and mechanistic insight into dendritic cell supply chain in obesity-associated airway inflammation.}, journal={Frontiers in Immunology}, publisher={Frontiers Media SA}, author={Jaiswal, Anil Kumar and Makhija, Sangeet and Stahr, Natalie and Sandey, Maninder and Suryawanshi, Amol and Saxena, Ankit and Dagur, Pradeep K. and McCoy, J. Philip and Levine, Stewart J. and Mishra, Amarjit}, year={2020}, month={Feb} }
 @article{jaiswal_makhija_stahr_sandey_suryawanshi_mishra_2020, title={Pyruvate kinase M2 in lung APCs regulates Alternaria-induced airway inflammation}, volume={225}, ISSN={0171-2985}, url={http://dx.doi.org/10.1016/j.imbio.2020.151956}, DOI={10.1016/j.imbio.2020.151956}, abstractNote={Sensitivity to allergenic fungi (Alternaria alternata) is associated with acute, severe asthma attacks. Antigen presenting cells (APCs) in the lung sense environmental perturbations that induce cellular stress and metabolic changes and are critical for allergic airway inflammation. However, the mechanisms underlying such environmental sensing by APCs in the lung remains unclear. Here we show that acute Alternaria challenge rapidly induces neutrophil accumulation in airways, and alter expressions of Pyruvate Kinase (PKM2) and hypoxia-inducible factor -1α (Hif-1α) that correlates with proinflammatory mediator release. Blockade of IL33 signaling in vivo led to reduce oxidative stress and glycolysis in lung APCs. Lung-specific ablation of CD11c+ cells abrogates Alternaria-induced neutrophil accumulation and inflammation. Furthermore, administration of Alternaria into the airways stimulated APCs and elevate the expression of Glut-1. Mechanistically, we establish that PKM2 is a critical modulator of lung APC activation in Alternaria-induced acute inflammation. Allosteric activation of PKM2 by a small molecule ML265 or siRNA-mediated knock down correlated negatively with glycolysis and activation of APCs. These results collectively demonstrates that PKM2-mediated glycolytic reprogramming by fungal allergen Alternaria influences lung APC activation, thereby promotes acute airway inflammation. Our data support a model in which Alternaria sensitization in airways induce a circuitry of glycolysis and PKM2 regulation that confers an acute activation of APCs in the lung, whose targeting might represent a strategy for asthma treatment.}, number={4}, journal={Immunobiology}, publisher={Elsevier BV}, author={Jaiswal, Anil Kumar and Makhija, Sangeet and Stahr, Natalie and Sandey, Maninder and Suryawanshi, Amol and Mishra, Amarjit}, year={2020}, month={Jul}, pages={151956} }
 @article{suryawanshi_hussein_prasad_manicassamy_2020, title={Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity}, volume={11}, ISSN={1664-3224}, url={http://dx.doi.org/10.3389/fimmu.2020.00122}, DOI={10.3389/fimmu.2020.00122}, abstractNote={Dendritic cells (DCs) control the strength and quality of antigen-specific adaptive immune responses. This is critical for launching robust immunity against invading pathogens while maintaining a state of tolerance to self-antigen. However, this also represents a fundamental barrier to anti-tumor immune responses and cancer immunotherapy. DCs in the tumor microenvironment (TME) play a key role in this process. The factors in the TME and signaling networks that program DCs to a regulatory state are not fully understood. Recent advances point to novel mechanisms by which the canonical Wnt signaling cascade in DCs regulates immune suppression and the same pathway in tumors is associated with the evasion of antitumor immunity. Here, we review these recent advances, in the context of the pleiotropic effects of the Wnts in shaping anti-tumor immune responses by modulating DC functions. In addition, we will discuss how Wnt/β-catenin pathway in DCs can be targeted for successful cancer immunotherapy.}, journal={Frontiers in Immunology}, publisher={Frontiers Media SA}, author={Suryawanshi, Amol and Hussein, Mohamed S. and Prasad, Puttur D. and Manicassamy, Santhakumar}, year={2020}, month={Feb} }
 @article{jaiswal_sandey_suryawanshi_cattley_mishra_2019, title={Dimethyl fumarate abrogates dust mite‐induced allergic asthma by altering dendritic cell function}, volume={7}, ISSN={2050-4527 2050-4527}, url={http://dx.doi.org/10.1002/iid3.262}, DOI={10.1002/iid3.262}, abstractNote={Abstract Introduction Allergic asthma is the most common inflammatory disease of upper airways. Airway dendritic cells (DCs) are key antigen presenting cells that regulate T helper 2 (Th2)‐dependent allergic inflammation. Recent studies have shown critical role of airway DCs in the induction of Th2‐mediated allergic inflammation and are attractive therapeutic targets in asthma. However, molecular signaling mechanism that regulate DCs function to Th2 immune responses are poorly understood. Here we aim to evaluate the immunomodulatory effect of dimethyl fumarate (DMF), an FDA approved small molecule drug, in the house dust mite (HDM)‐induced experimental model of allergic asthma. Methods DMF was administered intranasally in the challenge period of HDM‐induced murine model of experimental asthma. Airway inflammation, airway hyperreactivity, Th2/Th1 cytokine were assessed. The effect of DMF on DC function was further evaluated by adoptive transfer of HDM‐pulsed DMF treated DCs to wild‐type naïve mice. Results DMF treatment significantly reduced HDM‐induced airway inflammation, mucous cell metaplasia, and airway hyperactivity to inhaled methacholine. Mechanistically, DMF interferes with the migration of lung DCs to draining mediastinal lymph nodes, thereby attenuates the induction of allergic sensitization and Th2 immune response. Notably, adoptive transfer of DMF treated DCs to naïve mice with HDM challenge similarly reduces the features of allergic asthma. Conclusion This identifies a novel function of DMF on DC‐mediated adaptive immune responses in the setting of HDM‐induced airway inflammation. Taken together, our results offer a mechanistic rationale for DMF use to target DCs in local lung environment as antiasthmatic therapy.}, number={3}, journal={Immunity, Inflammation and Disease}, publisher={Wiley}, author={Jaiswal, Anil K. and Sandey, Maninder and Suryawanshi, Amol and Cattley, Russell C. and Mishra, Amarjit}, year={2019}, month={Jul}, pages={201–213} }
 @article{ranganathan_shanmugam_swafford_suryawanshi_bhattacharjee_hussein_koni_prasad_kurago_thangaraju_et al._2018, title={GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis}, volume={200}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1700604}, DOI={10.4049/jimmunol.1700604}, abstractNote={Abstract At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food Ags. The molecular mechanisms underlying this phenomenon remain poorly understood. In this study, we report that signaling by GPR81, a receptor for lactate, in colonic dendritic cells and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation.}, number={5}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Ranganathan, Punithavathi and Shanmugam, Arulkumaran and Swafford, Daniel and Suryawanshi, Amol and Bhattacharjee, Pushpak and Hussein, Mohamed S. and Koni, Pandelakis A. and Prasad, Puttur D. and Kurago, Zoya B. and Thangaraju, Muthusamy and et al.}, year={2018}, month={Mar}, pages={1781–1789} }
 @article{sampson_suryawanshi_chen_rabinovich_panjwani_2016, title={Galectin-8 promotes regulatory T-cell differentiation by modulating IL-2 and TGFβ signaling}, volume={94}, DOI={10.1038/icb.2016.8}, abstractNote={Correction to: Immunology and Cell Biology (2016) 94, 213–219; doi:10.1038/icb.2015.72; published online 18 August 2015 The following sentence in the Discussion section of this paper was published incorrectly: Alternatively, Gals may directly ligate and activate their receptors independent of lattice formation. Specifically, the words ‘independent of lattice formation’ should be deleted. The corrected sentence as it appears in the Discussion on page 217 of this issue reads as follows: Alternatively, Gals may directly ligate and activate their receptors. The authors wish to apologize for their error.}, number={2}, journal={Immunology and Cell Biology}, publisher={Wiley}, author={Sampson, James F and Suryawanshi, Amol and Chen, Wei-Sheng and Rabinovich, Gabriel A and Panjwani, Noorjahan}, year={2016}, month={Feb}, pages={220–220} }
 @article{manoharan_suryawanshi_hong_ranganathan_shanmugam_ahmad_swafford_manicassamy_ramesh_koni_et al._2016, title={Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine}, volume={196}, DOI={10.4049/jimmunol.1501489}, abstractNote={Abstract Dietary lipids and their metabolites activate members of the peroxisome proliferative–activated receptor (PPAR) family of transcription factors and are critical for colonic health. The PPARα isoform plays a vital role in regulating inflammation in various disease settings, but its role in intestinal inflammation, commensal homeostasis, and mucosal immunity in the gut are unclear. In this study, we demonstrate that the PPARα pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the antimicrobial peptides RegIIIβ, RegIIIγ, and calprotectin. Additionally, the PPARα pathway is critical for imparting regulatory phenotype in intestinal macrophages. PPARα deficiency in mice led to commensal dysbiosis in the gut, resulting in a microbiota-dependent increase in the expression of inflammatory cytokines and enhanced susceptibility to intestinal inflammation. Pharmacological activation of this pathway decreased the expression of inflammatory cytokines and ameliorated colonic inflammation. Taken together, these findings identify a new important innate immune function for the PPARα signaling pathway in regulating intestinal inflammation, mucosal immunity, and commensal homeostasis. Thus, the manipulation of the PPARα pathway could provide novel opportunities for enhancing mucosal immunity and treating intestinal inflammation.}, number={11}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Manoharan, Indumathi and Suryawanshi, Amol and Hong, Yuan and Ranganathan, Punithavathi and Shanmugam, Arulkumaran and Ahmad, Shamim and Swafford, Daniel and Manicassamy, Balaji and Ramesh, Ganesan and Koni, Pandelakis A. and et al.}, year={2016}, month={Apr}, pages={4739–4749} }
 @article{suryawanshi_tadagavadi_swafford_manicassamy_2016, title={Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer}, volume={7}, ISSN={1664-3224}, url={http://dx.doi.org/10.3389/fimmu.2016.00460}, DOI={10.3389/fimmu.2016.00460}, abstractNote={The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic auto-immune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade anti-tumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β -catenin pathway can be targeted for successful therapeutic interventions in various human diseases.}, journal={Frontiers in Immunology}, publisher={Frontiers Media SA}, author={Suryawanshi, Amol and Tadagavadi, Raghu K. and Swafford, Daniel and Manicassamy, Santhakumar}, year={2016}, month={Oct} }
 @article{kandasamy_suryawanshi_tundup_perez_schmolke_manicassamy_manicassamy_2016, title={RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection}, volume={12}, ISSN={1553-7374}, url={http://dx.doi.org/10.1371/journal.ppat.1005754}, DOI={10.1371/journal.ppat.1005754}, abstractNote={Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 –MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains.}, number={7}, journal={PLOS Pathogens}, publisher={Public Library of Science (PLoS)}, author={Kandasamy, Matheswaran and Suryawanshi, Amol and Tundup, Smanla and Perez, Jasmine T. and Schmolke, Mirco and Manicassamy, Santhakumar and Manicassamy, Balaji}, editor={Subbarao, KantaEditor}, year={2016}, month={Jul}, pages={e1005754} }
 @article{suryawanshi_manoharan_hong_swafford_majumdar_taketo_manicassamy_koni_thangaraju_sun_et al._2015, title={Canonical Wnt Signaling in Dendritic Cells Regulates Th1/Th17 Responses and Suppresses Autoimmune Neuroinflammation}, volume={194}, DOI={10.4049/jimmunol.1402691}, abstractNote={Abstract Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein [LRP]5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin–mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.}, number={7}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Manoharan, Indumathi and Hong, Yuan and Swafford, Daniel and Majumdar, Tanmay and Taketo, M. Mark and Manicassamy, Balaji and Koni, Pandelakis A. and Thangaraju, Muthusamy and Sun, Zuoming and et al.}, year={2015}, month={Feb}, pages={3295–3304} }
 @article{hong_manoharan_suryawanshi_shanmugam_swafford_ahmad_chinnadurai_manicassamy_he_mellor_et al._2015, title={Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity}, volume={5}, DOI={10.1080/2162402x.2015.1115941}, abstractNote={The tumor microenvironment (TME) contains high levels of the Wnt family of ligands, and aberrant Wnt-signaling occurs in many tumors. Past studies have been directed toward how the Wnt signaling cascade regulates cancer development, progression and metastasis. However, its effects on host antitumor immunity remain unknown. In this report, we show that Wnts in the TME condition dendritic cells (DCs) to a regulatory state and suppress host antitumor immunity. DC-specific deletion of Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in mice markedly delayed tumor growth and enhanced host antitumor immunity. Mechanistically, loss of LRP5/6-mediated signaling in DCs resulted in enhanced effector T cell differentiation and decreased regulatory T cell differentiation. This was due to increased production of pro-inflammatory cytokines and decreased production of IL-10, TGF-β1 and retinoic acid (RA). Likewise, pharmacological inhibition of the Wnts' interaction with its cognate co-receptors LRP5/6 and Frizzled (Fzd) receptors had similar effects on tumor growth and effector T cell responses. Moreover, blocking Wnt-signaling in DCs resulted in enhanced capture of tumor-associated antigens and efficient cross-priming of CD8+ T cells. Hence, blocking the Wnt pathway represents a potential therapeutic to overcome tumor-mediated immune suppression and augment antitumor immunity.}, number={4}, journal={OncoImmunology}, publisher={Informa UK Limited}, author={Hong, Yuan and Manoharan, Indumathi and Suryawanshi, Amol and Shanmugam, Arulkumaran and Swafford, Daniel and Ahmad, Shamim and Chinnadurai, Raghavan and Manicassamy, Balaji and He, Yukai and Mellor, Andrew L. and et al.}, year={2015}, pages={e1115941} }
 @article{sampson_hasegawa_mulki_suryawanshi_jiang_chen_rabinovich_connor_panjwani_2015, title={Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response}, volume={10}, DOI={10.1371/journal.pone.0130772}, abstractNote={Galectins have emerged as potent immunoregulatory agents that control chronic inflammation through distinct mechanisms. Here, we report that treatment with Galectin-8 (Gal-8), a tandem-repeat member of the galectin family, reduces retinal pathology and prevents photoreceptor cell damage in a murine model of experimental autoimmune uveitis. Gal-8 treatment increased the number of regulatory T cells (Treg) in both the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of Treg cells in the dLN and retina of Gal-8 treated animals expressed the inhibitory coreceptor cytotoxic T lymphocyte antigen (CTLA)-4, the immunosuppressive cytokine IL-10, and the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were primarily inducible Treg cells that lack the expression of neuropilin-1. In addition, Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type (TH) 1 and TH17 cells. The effect of Gal-8 on T cell differentiation and/or function was specific for tissues undergoing an active immune response, as Gal-8 treatment had no effect on T cell populations in the spleen. Given the need for rational therapies for managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only for treating retinal autoimmune diseases, but also for other TH1- and TH17-mediated inflammatory disorders.}, number={6}, journal={PLOS ONE}, publisher={Public Library of Science (PLoS)}, author={Sampson, James F. and Hasegawa, Eiichi and Mulki, Lama and Suryawanshi, Amol and Jiang, Shuhong and Chen, Wei-Sheng and Rabinovich, Gabriel A. and Connor, Kip M. and Panjwani, Noorjahan}, editor={Ashour, Hossam MEditor}, year={2015}, month={Jun}, pages={e0130772} }
 @article{suryawanshi_cao_sampson_panjwani_2014, title={IL-17A–Mediated Protection againstAcanthamoebaKeratitis}, volume={194}, DOI={10.4049/jimmunol.1302707}, abstractNote={Abstract Acanthamoeba keratitis (AK) is a very painful and vision-impairing infection of the cornea that is difficult to treat. Although past studies have indicated a critical role of neutrophils and macrophages in AK, the relative contribution of the proinflammatory cytokine, IL-17A, that is essential for migration, activation, and function of these cells into the cornea is poorly defined. Moreover, the role of the adaptive immune response, particularly the contribution of CD4+ T cell subsets, Th17 and regulatory T cells , in AK is yet to be understood. In this report, using a mouse corneal intrastromal injection-induced AK model, we show that Acanthamoeba infection induces a strong CD4+ T effector and regulatory T cell response in the cornea and local draining lymph nodes. We also demonstrate that corneal Acanthamoeba infection induces IL-17A expression and that IL-17A is critical for host protection against severe AK pathology. Accordingly, IL-17A neutralization in Acanthamoeba-infected wild-type mice or Acanthamoeba infection of mice lacking IL-17A resulted in a significantly increased corneal AK pathology, increased migration of inflammatory cells at the site of inflammation, and a significant increase in the effector CD4+ T cell response in draining lymph nodes. Thus, in sharp contrast with other corneal infections such as herpes and Pseudomonas aeruginosa keratitis where IL-17A exacerbates corneal pathology and inflammation, the findings presented in this article suggest that IL-17A production after Acanthamoeba infection plays an important role in host protection against invading parasites.}, number={2}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Cao, Zhiyi and Sampson, James F. and Panjwani, Noorjahan}, year={2014}, pages={650–663} }
 @article{suryawanshi_manicassamy_2015, title={Tumors induce immune tolerance through activation of β-catenin/TCF4 signaling in dendritic cells: A novel therapeutic target for cancer immunotherapy}, volume={4}, DOI={10.1080/2162402x.2015.1052932}, abstractNote={Tumors promote immune suppression and dendritic cells (DCs) play a key role in this. However, signaling networks that program DCs to induce immune suppression are unknown. In our recent study, we showed that tumors activate β-catenin/TCF4 in DCs programming them to a regulatory state, which promotes T regulatory responses while suppresses effector T cell responses. Thus, targeting DCs-β-catenin pathway represents a promising target for anticancer immunotherapy.}, number={12}, journal={OncoImmunology}, publisher={Informa UK Limited}, author={Suryawanshi, Amol and Manicassamy, Santhakumar}, year={2015}, month={Jun}, pages={e1052932} }
 @article{hong_manoharan_suryawanshi_majumdar_angus-hill_koni_manicassamy_mellor_munn_manicassamy_2015, title={β-Catenin Promotes Regulatory T-cell Responses in Tumors by Inducing Vitamin A Metabolism in Dendritic Cells}, volume={75}, ISSN={0008-5472 1538-7445}, url={http://dx.doi.org/10.1158/0008-5472.can-14-2377}, DOI={10.1158/0008-5472.can-14-2377}, abstractNote={Abstract Tumors actively suppress antitumor immunity, creating formidable barriers to successful cancer immunotherapy. The molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that dendritic cells (DC) in the tumor microenvironment acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives regulatory T-cell responses and immune tolerance. Tolerogenic responses were dependent on induction of vitamin A–metabolizing enzymes via the β-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of β-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A–metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy. Cancer Res; 75(4); 656–65. ©2015 AACR.}, number={4}, journal={Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Hong, Yuan and Manoharan, Indumathi and Suryawanshi, Amol and Majumdar, Tanmay and Angus-Hill, Melinda L. and Koni, Pandelakis A. and Manicassamy, Balaji and Mellor, Andrew L. and Munn, David H. and Manicassamy, Santhakumar}, year={2015}, month={Feb}, pages={656–665} }
 @article{reddy_sehrawat_suryawanshi_rajasagi_khatri_rouse_2014, title={An Approach to Control Relapse of Inflammatory Lesions after Discontinuation of Primary Therapy}, volume={9}, DOI={10.1371/journal.pone.0098051}, abstractNote={Long-term treatment with the fungal metabolite drug FTY720 (Fingolimod) was shown to be highly effective in controlling viral immunopathological lesions. However, in this report we show that the anti-inflammatory effect of FTY720 in herpes simplex virus-1 (HSV-1) induced ocular inflammation is lost upon the discontinuation of treatment and lesions rapidly recurred. The lesions that developed after FTY720 treatment withdrawal involved mainly Th17 cells rather than Th1 cells explained in part by differential expression of surface CD103, an integrin that permits migration of effector cells to inflammatory sites. The expression of IL-6, a proinflammatory cytokine involved in the generation of Th17 cells, was found to be increased in FTY treated mice as compared to controls and this effect could be abrogated upon administration of neutralizing antibody to IL-6. Furthermore, IL-17RKO mice failed to show the recurrence of stromal keratitis (SK) lesions upon FTY720 withdrawal. These results indicate that approaches such as neutralization of proinflammatory cytokines might be considered along with FTY720 treatment if interruption of drug therapy becomes necessary.}, number={5}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Reddy, Pradeep B. J. and Sehrawat, Sharvan and Suryawanshi, Amol and Rajasagi, Naveen K. and Khatri, Madhu and Rouse, Barry T.}, editor={Tripp, RalphEditor}, year={2014}, month={May}, pages={e98051} }
 @article{manoharan_hong_suryawanshi_angus-hill_sun_mellor_munn_manicassamy_2014, title={TLR2-Dependent Activation of β-Catenin Pathway in Dendritic Cells Induces Regulatory Responses and Attenuates Autoimmune Inflammation}, volume={193}, DOI={10.4049/jimmunol.1400614}, abstractNote={Abstract Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.}, number={8}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Manoharan, Indumathi and Hong, Yuan and Suryawanshi, Amol and Angus-Hill, Melinda L. and Sun, Zuoming and Mellor, Andrew L. and Munn, David H. and Manicassamy, Santhakumar}, year={2014}, month={Sep}, pages={4203–4213} }
 @article{suryawanshi_cao_thitiprasert_zaidi_panjwani_2013, title={Galectin-1–Mediated Suppression of <i>Pseudomonas aeruginosa</i>–Induced Corneal Immunopathology}, volume={190}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1203501}, DOI={10.4049/jimmunol.1203501}, abstractNote={Abstract Corneal infection with Pseudomonas aeruginosa leads to a severe immunoinflammatory lesion, often causing vision impairment and blindness. Although past studies have indicated a critical role for CD4+ T cells, particularly Th1 cells, in corneal immunopathology, the relative contribution of recently discovered Th17 and regulatory T cells is undefined. In this study, we demonstrate that after corneal P. aeruginosa infection, both Th1 and Th17 cells infiltrate the cornea with increased representation of Th17 cells. In addition to Th1 and Th17 cells, regulatory T cells also migrate into the cornea during early as well as late stages of corneal pathology. Moreover, using galectin-1 (Gal-1), an immunomodulatory carbohydrate-binding molecule, we investigated whether shifting the balance among various CD4+ T cell subsets can modulate P. aeruginosa–induced corneal immunopathology. We demonstrate in this study that local recombinant Gal-1 (rGal-1) treatment by subconjunctival injections significantly diminishes P. aeruginosa–mediated corneal inflammation through multiple mechanisms. Specifically, in our study, rGal-1 treatment significantly diminished corneal infiltration of total CD45+ T cells, neutrophils, and CD4+ T cells. Furthermore, rGal-1 treatment significantly reduced proinflammatory Th17 cell response in the cornea as well as local draining lymph nodes. Also, rGal-1 therapy promoted anti-inflammatory Th2 and IL-10 response in secondary lymphoid organs. Collectively, our results indicate that corneal P. aeruginosa infection induces a strong Th17-mediated corneal pathology, and treatment with endogenously derived protein such as Gal-1 may be of therapeutic value for the management of bacterial keratitis, a prevalent cause of vision loss and blindness in humans worldwide.}, number={12}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Cao, Zhiyi and Thitiprasert, Thananya and Zaidi, Tanveer S. and Panjwani, Noorjahan}, year={2013}, month={Jun}, pages={6397–6409} }
 @article{giménez_suryawanshi_rouse_2013, title={Pathogenesis of herpes stromal keratitis – A focus on corneal neovascularization}, volume={33}, url={http://europepmc.org/abstract/med/22892644}, DOI={10.1016/j.preteyeres.2012.07.002}, abstractNote={The cornea is a complex sensory organ that must maintain its transparency for optimal vision. Infections such as with herpes simplex virus can result in blinding immunoinflammatory reactions referred to as herpes stromal keratitis (HSK). In this review we discuss the pathogenesis of HSK referring to work mainly done using animal model systems. We briefly discuss the role of multiple cell types and soluble mediators but focus on the critical role of corneal vascularization (CV) in contributing to corneal damage. We describe how VEGF and other angiogenic molecules are induced following infection and discuss the many ways by which CV can be controlled. Speculations are made regarding future approaches that could improve the management of HSK.}, journal={Progress in Retinal and Eye Research}, publisher={Elsevier BV}, author={Giménez, Fernanda and Suryawanshi, Amol and Rouse, Barry T.}, year={2013}, month={Mar}, pages={1–9} }
 @article{rajasagi_suryawanshi_sehrawat_reddy_mulik_hirashima_rouse_2012, title={Galectin-1 Reduces the Severity of Herpes Simplex Virus-Induced Ocular Immunopathological Lesions}, volume={188}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1103063}, DOI={10.4049/jimmunol.1103063}, abstractNote={Abstract Stromal keratitis is a chronic immunopathological lesion of the eye caused by HSV-1 infection that can result in blindness. Because the inflammatory lesions are primarily orchestrated by Th1 cells, and to a lesser extent by Th17 cells, inhibiting their activity represents a useful form of therapy. In this study we evaluated the therapeutic potential of galectin-1 (gal-1), an endogenous lectin that in some autoimmune diseases was shown to suppress the functions of Th1 and Th17 cells. Treatment was begun at different times after ocular infection with HSV and the outcome was assessed clinically as well as for effects on various immune parameters. Treatment with recombinant gal-1 significantly diminished stromal keratitis lesion severity and the extent of corneal neovascularization. Treated mice had reduced numbers of IFN-γ– and IL-17–producing CD4+ T cells, as well as neutrophil infiltration in the cornea. Furthermore, disease severity was greater in gal-1 knockout mice compared with their wild-type counterparts. The many effects of gal-1 treatment include reduction in the production of proinflammatory cytokines and chemokines, increased production of IL-10, and inhibitory effects on molecules involved in neovascularization. To our knowledge, our findings are the first to show that gal-1 treatment represents a useful approach to control lesion severity in a virally induced immunopathological disease.}, number={9}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Rajasagi, Naveen K. and Suryawanshi, Amol and Sehrawat, Sharvan and Reddy, Pradeep B. J. and Mulik, Sachin and Hirashima, Mitsuomi and Rouse, Barry T.}, year={2012}, month={May}, pages={4631–4643} }
 @article{suryawanshi_veiga-parga_reddy_rajasagi_rouse_2012, title={IL-17A Differentially Regulates Corneal Vascular Endothelial Growth Factor (VEGF)-A and Soluble VEGF Receptor 1 Expression and Promotes Corneal Angiogenesis after Herpes Simplex Virus Infection}, volume={188}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1102602}, DOI={10.4049/jimmunol.1102602}, abstractNote={Abstract Ocular infection with HSV causes corneal neovascularization (CV), an essential step in the pathogenesis of the blinding immunoinflammatory lesion stromal keratitis. The infection results in IL-17A production, which contributes to CV in ways that together serve to shift the balance between corneal concentrations of vascular endothelial growth factor A (VEGF-A) and the soluble vascular endothelial growth factor receptor 1 molecule, which binds to VEGF-A and blocks its function (a so-called VEGF trap). Accordingly, animals lacking responses to IL-17A signaling, either because of IL-17 receptor A knockout or wild-type animals that received neutralizing mAb to IL-17A, had diminished CV, compared with controls. The procedures reduced VEGF-A protein levels but had no effect on the levels of soluble vascular endothelial growth factor receptor 1. Hence the VEGF trap was strengthened. IL-17A also caused increased CXCL1/KC synthesis, which attracts neutrophils to the inflammatory site. Neutrophils further influenced the extent of CV by acting as an additional source of VEGF-A, as did metalloproteinase enzymes that degrade the soluble receptor, inhibiting its VEGF-blocking activity. Our results indicate that suppressing the expression of IL-17A, or increasing the activity of the VEGF trap, represents a useful approach to inhibiting CV and the control of an ocular lesion that is an important cause of human blindness.}, number={7}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Veiga-Parga, Tamara and Reddy, Pradeep B. J. and Rajasagi, Naveen K. and Rouse, Barry T.}, year={2012}, month={Apr}, pages={3434–3446} }
 @article{veiga-parga_suryawanshi_mulik_giménez_sharma_sparwasser_rouse_2012, title={On the Role of Regulatory T Cells during Viral-Induced Inflammatory Lesions}, volume={189}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1202322}, DOI={10.4049/jimmunol.1202322}, abstractNote={Abstract Ocular HSV-1 infection can result in stromal keratitis, a blinding immunoinflammatory lesion that represents an immunopathological response to the infection. CD4+ T cells are the main orchestrators, and lesions are more severe if the regulatory T cell (Treg) response is compromised from the onset of infection. Little is known about the role of Foxp3+CD4+ Tregs during ongoing inflammatory reactions, which is the topic of this article. We used DEREG mice and depleted Tregs at different times postinfection. We show that lesions became more severe even when depletion was begun in the clinical phase of the disease. This outcome was explained both by Tregs’ influence on the activity of inflammatory effector T cells at the lesion site and by an effect in lymphoid tissues that led to reduced numbers of effectors and less trafficking of T cells and neutrophils to the eye. Our results demonstrate that Tregs can beneficially influence the impact of ongoing tissue-damaging responses to a viral infection and imply that therapies boosting Treg function in the clinical phase hold promise for controlling a lesion that is an important cause of human blindness.}, number={12}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Veiga-Parga, Tamara and Suryawanshi, Amol and Mulik, Sachin and Giménez, Fernanda and Sharma, Shalini and Sparwasser, Tim and Rouse, Barry T.}, year={2012}, month={Dec}, pages={5924–5933} }
 @article{j reddy_schreiber_rajasagi_suryawanshi_mulik_veiga-parga_niki_hirashima_podack_rouse_2012, title={TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions}, volume={86}, ISSN={0022-538X 1098-5514}, url={http://dx.doi.org/10.1128/jvi.01391-12}, DOI={10.1128/jvi.01391-12}, abstractNote={ABSTRACT Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4 + T cells. Hence, targeting proinflammatory CD4 + T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naïve animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4 + gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.}, number={19}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={J Reddy, Pradeep B. and Schreiber, Taylor H. and Rajasagi, Naveen K. and Suryawanshi, Amol and Mulik, Sachin and Veiga-Parga, Tamara and Niki, Toshiro and Hirashima, Mitsuomi and Podack, Eckhard R. and Rouse, Barry T.}, year={2012}, month={Oct}, pages={10606–10620} }
 @article{mulik_sharma_suryawanshi_veiga-parga_reddy_rajasagi_rouse_2011, title={Activation of Endothelial Roundabout Receptor 4 Reduces the Severity of Virus-Induced Keratitis}, volume={186}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1100014}, DOI={10.4049/jimmunol.1100014}, abstractNote={Abstract Antiangiogenic molecules exert a feedback control to restrain pathological angiogenesis, which includes physical binding or inhibition of angiogenic signaling in blood vessel endothelial cells. The latter is the case in which Slit2 ligand-dependent activation of the blood vessel endothelial cell receptor roundabout 4 (Robo4) occurs. In this study, we demonstrate that Robo4 receptors are upregulated following HSV infection of the eye on the majority of the new blood vessel endothelial cells that occur in the corneal stroma. However, expression levels of the ligand for Robo4 receptors, Slit2, was not significantly increased during the disease process, and the knockdown of Slit2 gene expression using lentiviral short hairpin RNAs had no effect on the extent of pathological angiogenesis. In contrast, providing additional Slit2 protein by subconjunctival administration resulted in significantly reduced angiogenesis. The Slit2 binding to Robo4 was shown to block the downstream vascular endothelial growth factor signaling molecules Arf 6 and Rac 1 and reduce the antiapoptotic molecule Bcl-xL in blood vessel endothelial cells. Our results indicate that augmenting the host Robo4/Slit2 system could provide a useful therapeutic approach to control pathological angiogenesis associated with HSV induced stromal keratitis.}, number={12}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Mulik, Sachin and Sharma, Shalini and Suryawanshi, Amol and Veiga-Parga, Tamara and Reddy, Pradeep B. J. and Rajasagi, Naveen K. and Rouse, Barry T.}, year={2011}, month={Jun}, pages={7195–7204} }
 @article{sharma_mulik_kumar_suryawanshi_rouse_2011, title={An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology}, volume={85}, ISSN={0022-538X 1098-5514}, url={http://dx.doi.org/10.1128/jvi.00034-11}, DOI={10.1128/jvi.00034-11}, abstractNote={ABSTRACT Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4 + T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world.}, number={12}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Sharma, Shalini and Mulik, Sachin and Kumar, Naveen and Suryawanshi, Amol and Rouse, Barry T.}, year={2011}, month={Jun}, pages={5995–6007} }
 @article{rajasagi_reddy_suryawanshi_mulik_gjorstrup_rouse_2011, title={Controlling Herpes Simplex Virus-Induced Ocular Inflammatory Lesions with the Lipid-Derived Mediator Resolvin E1}, volume={186}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1003456}, DOI={10.4049/jimmunol.1003456}, abstractNote={Abstract Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by HSV-1 infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin E1 (RvE1), an endogenous lipid mediator, was shown to promote resolution in several inflammatory disease models. In the current report, we determined whether RvE1 administration begun at different times after ocular infection of mice with HSV could influence the severity of SK lesions. Treatment with RvE1 significantly reduced the extent of angiogenesis and SK lesions that occurred. RvE1-treated mice had fewer numbers of inflammatory cells that included Th1 and Th17 cells as well as neutrophils in the cornea. The mechanisms by which RvE1 acts appear to be multiple. These included reducing the influx of neutrophils and pathogenic CD4+ T cells, increasing production of the anti-inflammatory cytokine IL-10, and inhibitory effects on the production of proinflammatory mediators and molecules, such as IL-6, IFN-γ, IL-17, KC, VEGF-A, MMP-2, and MMP-9, that are involved in corneal neovascularization and SK pathogenesis. These findings are, to our knowledge, the first to show that RvE1 treatment could represent a novel approach to control lesion severity in a virally induced immunopathological disease.}, number={3}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Rajasagi, Naveen K. and Reddy, Pradeep B. J. and Suryawanshi, Amol and Mulik, Sachin and Gjorstrup, Per and Rouse, Barry T.}, year={2011}, month={Feb}, pages={1735–1746} }
 @article{veiga-parga_suryawanshi_rouse_2011, title={Controlling Viral Immuno-Inflammatory Lesions by Modulating Aryl Hydrocarbon Receptor Signaling}, volume={7}, url={http://europepmc.org/abstract/med/22174686}, DOI={10.1371/journal.ppat.1002427}, abstractNote={Ocular herpes simplex virus infection can cause a blinding CD4+ T cell orchestrated immuno-inflammatory lesion in the cornea called Stromal Keratitis (SK). A key to controlling the severity of SK lesions is to suppress the activity of T cells that orchestrate lesions and enhance the representation of regulatory cells that inhibit effector cell function. In this report we show that a single administration of TCDD (2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin), a non-physiological ligand for the AhR receptor, was an effective means of reducing the severity of SK lesions. It acted by causing apoptosis of Foxp3- CD4+ T cells but had no effect on Foxp3+ CD4+ Tregs. TCDD also decreased the proliferation of Foxp3- CD4+ T cells. The consequence was an increase in the ratio of Tregs to T effectors which likely accounted for the reduced inflammatory responses. In addition, in vitro studies revealed that TCDD addition to anti-CD3/CD28 stimulated naïve CD4+ T cells caused a significant induction of Tregs, but inhibited the differentiation of Th1 and Th17 cells. Since a single TCDD administration given after the disease process had been initiated generated long lasting anti-inflammatory effects, the approach holds promise as a therapeutic means of controlling virus induced inflammatory lesions.}, number={12}, journal={PLoS Pathogens}, publisher={Public Library of Science (PLoS)}, author={Veiga-Parga, Tamara and Suryawanshi, Amol and Rouse, Barry T.}, editor={Wherry, E. JohnEditor}, year={2011}, pages={e1002427} }
 @article{reddy_sehrawat_suryawanshi_rajasagi_mulik_hirashima_rouse_2011, title={Influence of Galectin-9/Tim-3 Interaction on Herpes Simplex Virus-1 Latency}, volume={187}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1102105}, DOI={10.4049/jimmunol.1102105}, abstractNote={Abstract After HSV-1 infection, CD8+ T cells accumulate in the trigeminal ganglion (TG) and participate in the maintenance of latency. However, the mechanisms underlying intermittent virus reactivation are poorly understood. In this study, we demonstrate the role of an inhibitory interaction between T cell Ig and mucin domain-containing molecule 3 (Tim-3)–expressing CD8+ T cells and galectin 9 (Gal-9) that could influence HSV-1 latency and reactivation. Accordingly, we show that most Kb-gB tetramer-specific CD8+ T cells in the TG of HSV-1–infected mice express Tim-3, a molecule that delivers negative signals to CD8+ T cells upon engagement of its ligand Gal-9. Gal-9 was also upregulated in the TG when replicating virus was present as well during latency. This could set the stage for Gal-9/Tim-3 interaction, and this inhibitory interaction was responsible for reduced CD8+ T cell effector function in wild-type mice. Additionally, TG cell cultures exposed to recombinant Gal-9 in the latent phase caused apoptosis of most CD8+ T cells. Furthermore, Gal-9 knockout TG cultures showed delayed and reduced viral reactivation as compared with wild-type cultures, demonstrating the greater efficiency of CD8+ T cells to inhibit virus reactivation in the absence of Gal-9. Moreover, the addition of recombinant Gal-9 to ex vivo TG cultures induced enhanced viral reactivation compared with untreated controls. Our results demonstrate that the host homeostatic mechanism mediated by Gal-9/Tim-3 interaction on CD8+ T cells can influence the outcome of HSV-1 latent infection, and manipulating Gal-9 signals might represent therapeutic means to inhibit HSV-1 reactivation from latency.}, number={11}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Reddy, Pradeep B. J. and Sehrawat, Sharvan and Suryawanshi, Amol and Rajasagi, Naveen K. and Mulik, Sachin and Hirashima, Mitsuomi and Rouse, Barry T.}, year={2011}, month={Dec}, pages={5745–5755} }
 @article{suryawanshi_mulik_sharma_reddy_sehrawat_rouse_2011, title={Ocular Neovascularization Caused by Herpes Simplex Virus Type 1 Infection Results from Breakdown of Binding between Vascular Endothelial Growth Factor A and Its Soluble Receptor}, volume={186}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1003239}, DOI={10.4049/jimmunol.1003239}, abstractNote={Abstract The normal cornea is transparent, which is essential for normal vision, and although the angiogenic factor vascular endothelial growth factor A (VEGF-A) is present in the cornea, its angiogenic activity is impeded by being bound to a soluble form of the VEGF receptor-1 (sVR-1). This report investigates the effect on the balance between VEGF-A and sVR-1 that occurs after ocular infection with HSV, which causes prominent neovascularization, an essential step in the pathogenesis of the vision-impairing lesion, stromal keratitis. We demonstrate that HSV-1 infection causes increased production of VEGF-A but reduces sVR-1 levels, resulting in an imbalance of VEGF-A and sVR-1 levels in ocular tissues. Moreover, the sVR-1 protein made was degraded by the metalloproteinase (MMP) enzymes MMP-2, -7, and -9 produced by infiltrating inflammatory cells that were principally neutrophils. Inhibition of neutrophils, inhibition of sVR-1 breakdown with the MMP inhibitor marimastat, and the provision of exogenous recombinant sVR-1 protein all resulted in reduced angiogenesis. Our results make the novel observation that ocular neovascularization resulting from HSV infection involves a change in the balance between VEGF-A and its soluble inhibitory receptor. Future therapies aimed to increase the production and activity of sVR-1 protein could benefit the management of stromal keratitis, an important cause of human blindness.}, number={6}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Mulik, Sachin and Sharma, Shalini and Reddy, Pradeep B. J. and Sehrawat, Sharvan and Rouse, Barry T.}, year={2011}, month={Mar}, pages={3653–3665} }
 @article{suryawanshi_veiga-parga_rajasagi_reddy_sehrawat_sharma_rouse_2011, title={Role of IL-17 and Th17 Cells in Herpes Simplex Virus-Induced Corneal Immunopathology}, volume={187}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.1100736}, DOI={10.4049/jimmunol.1100736}, abstractNote={Abstract HSV-1 infection of the cornea leads to a blinding immunoinflammatory lesion of the eye termed stromal keratitis (SK). Recently, IL-17–producing CD4+ T cells (Th17 cells) were shown to play a prominent role in many autoimmune conditions, but the role of IL-17 and/or of Th17 cells in virus immunopathology is unclear. In this study, we show that, after HSV infection of the cornea, IL-17 is upregulated in a biphasic manner with an initial peak production around day 2 postinfection and a second wave starting from day 7 postinfection with a steady increase until day 21 postinfection, a time point when clinical lesions are fully evident. Further studies demonstrated that innate cells, particularly γδ T cells, were major producers of IL-17 early after HSV infection. However, during the clinical phase of SK, the predominant source of IL-17 was Th17 cells that infiltrated the cornea only after the entry of Th1 cells. By ex vivo stimulation, the half fraction of IFN-γ–producing CD4+ T cells (Th1 cells) were HSV specific, whereas very few Th17 cells responded to HSV stimulation. The delayed influx of Th17 cells in the cornea was attributed to the local chemokine and cytokine milieu. Finally, HSV infection of IL-17R knockout mice as well as IL-17 neutralization in wild-type mice showed diminished SK severity. In conclusion, our results show that IL-17 and Th17 cells contribute to the pathogenesis of SK, the most common cause of infectious blindness in the Western world.}, number={4}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Suryawanshi, Amol and Veiga-Parga, Tamara and Rajasagi, Naveen K. and Reddy, Pradeep Babu Jagdeesh and Sehrawat, Sharvan and Sharma, Shalini and Rouse, Barry T.}, year={2011}, month={Aug}, pages={1919–1930} }
 @article{sharma_sundararajan_suryawanshi_kumar_veiga-parga_kuchroo_thomas_sangster_rouse_2011, title={T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses}, volume={108}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1107087108}, DOI={10.1073/pnas.1107087108}, abstractNote={Reactions to pathogens are usually tuned to effect immunity and limit tissue damage. Several host counterinflammatory mechanisms inhibit tissue damage but these may also act to constrain the effectiveness of immunity to acute infections, as we demonstrate in mice acutely infected with influenza A virus (IAV). We show that compared with wild type (WT), galectin-9 knockout (G9KO) mice mounted a more robust acute phase virus-specific CD8 T-cell response as well as higher and more rapid virus-specific serum IgM, IgG, and IgA responses and also cleared virus more rapidly than did WT mice. Blocking galectin-9 signals to Tim-3-expressing cells using a Tim-3 fusion protein resulted in improved immune responses in WT mice. When IAV immune mice were challenged with a heterologous IAV, the secondary IAV-specific CD8 T-cell responses were four- to fivefold higher in G9KO compared with WT mice. Our results indicate that manipulating galectin signals may represent a convenient approach to improve immune responses to some vaccines.}, number={47}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Sharma, Shalini and Sundararajan, Aarthi and Suryawanshi, Amol and Kumar, Naveen and Veiga-Parga, Tamara and Kuchroo, Vijay K. and Thomas, Paul G. and Sangster, Mark Y. and Rouse, Barry T.}, year={2011}, month={Nov}, pages={19001–19006} }
 @article{sehrawat_reddy_rajasagi_suryawanshi_hirashima_rouse_2010, title={Galectin-9/TIM-3 Interaction Regulates Virus-Specific Primary and Memory CD8+ T Cell Response}, volume={6}, url={http://europepmc.org/abstract/med/20463811}, DOI={10.1371/journal.ppat.1000882}, abstractNote={In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8(+) T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with alpha-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8(+) T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8(+) T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3(+) CD8(+) T effector cells as well as the promotion of Foxp3(+) regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.}, number={5}, journal={PLoS Pathogens}, publisher={Public Library of Science (PLoS)}, author={Sehrawat, Sharvan and Reddy, Pradeep B. J. and Rajasagi, Naveen and Suryawanshi, Amol and Hirashima, Mitsuomi and Rouse, Barry T.}, editor={Hill, Ann B.Editor}, year={2010}, month={May}, pages={e1000882} }
 @article{naresha_suryawanshi_agarwal_singh_joshi_2009, title={Mapping the complement C1q binding site in Haemonchus contortus calreticulin}, volume={166}, ISSN={0166-6851}, url={http://dx.doi.org/10.1016/j.molbiopara.2009.02.007}, DOI={10.1016/j.molbiopara.2009.02.007}, abstractNote={Haemonchus contortus is an economically important gastrointestinal parasite of domestic animals. The parasite secretes calreticulin (CalR), a Ca++ binding protein which modulates the host immune response. One way by which this protein acts is by inhibiting the classical complement pathway by binding to complement C1q protein. Understanding CalR–C1q interaction is important to develop methods to enhance host immune response. In this study, we have mapped the regions in the N-domain of CalR that facilitates C1q binding by generating small recombinant fragments of the domain and using synthetic peptides. In addition to already identified C1q binding motifs in human CalR, two additional sites in the N-domain of H. contortus were revealed with the following sequences—GKYYDDAKRD and the AKFPKKFT. The significance of multiple C1q binding motifs in CalR is discussed in relation to host–parasite interactions.}, number={1}, journal={Molecular and Biochemical Parasitology}, publisher={Elsevier BV}, author={Naresha, S. and Suryawanshi, A. and Agarwal, M. and Singh, B.P. and Joshi, P.}, year={2009}, month={Jul}, pages={42–46} }
 @article{sehrawat_suryawanshi_hirashima_rouse_2009, title={Role of Tim-3/Galectin-9 Inhibitory Interaction in Viral-Induced Immunopathology: Shifting the Balance toward Regulators}, volume={182}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.0803673}, DOI={10.4049/jimmunol.0803673}, abstractNote={Abstract Controlling chronic immunoinflammatory diseases such as lesions in the eye caused by infection with HSV represents a therapeutic challenge. Since CD4+ T cells are the primary orchestrators of lesions, targeting activated CD4+ T cell subsets and increasing the representation of cells that express regulatory function would be a logical therapeutic approach. We show that this outcome can be achieved by therapy, systemic or local, with the lectin family member galectin-9. This molecule, which is a natural product of many cell types, acts as a ligand to the inhibitory molecule TIM-3 (T cell Ig and mucin-3) that is expressed by activated but not naive T cells. We show that 50% or more of T cells in ocular lesions caused by HSV in mice express TIM-3 and that blocking signals from its natural ligand with a mAb results in more severe lesions. More importantly, the provision of additional galectin-9, either systemically or more effectively by local subconjuctival administration, diminished the severity of stromal keratitis lesions as well as the extent of corneal neovascularization. Multiple mechanisms were involved in inhibitory effects. These included apoptosis of the orchestrating effector T cells with consequent reduction of proinflammatory cytokines and an increase in the representation of two separate subtypes of regulatory cells as well as inhibitory effects on the production of molecules involved in neovascularization, an essential component of stromal keratitis pathogenesis. Our results indicate that galectin-9 therapy may represent a useful approach to control HSV-induced lesions, the most common cause of infectious blindness in the Western world.}, number={5}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Sehrawat, Sharvan and Suryawanshi, Amol and Hirashima, Mitsuomi and Rouse, Barry T.}, year={2009}, month={Mar}, pages={3191–3201} }
 @article{sehrawat_suvas_sarangi_suryawanshi_rouse_2008, title={In Vitro-Generated Antigen-Specific CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup>Regulatory T Cells Control the Severity of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions}, volume={82}, ISSN={0022-538X 1098-5514}, url={http://dx.doi.org/10.1128/jvi.00697-08}, DOI={10.1128/jvi.00697-08}, abstractNote={ABSTRACT Generating and using regulatory T cells (Tregs) to modulate inflammatory disease represents a valuable approach to therapy but has not yet been applied as a means to control virus-induced immunopathological reactions. In this report, we developed a simplified technique that used unfractionated splenocytes as a precursor population and showed that stimulation under optimized conditions for 5 days with solid-phase anti-CD3 monoclonal antibody in the presence of transforming growth factor β (TGF-β) and interleukin-2 could induce up to 90% of CD4 + T cells to become Foxp3 + and able to mediate suppression in vitro. CD11c + dendritic cells were intricately involved in the conversion process and, once modified in the presence of TGF-β, could convert Foxp3 − CD4 + cells into Foxp3 + CD4 + cells by producing TGF-β. The converted cells had undergone cell division, and the majority of them expressed activation markers along with surface molecules that would facilitate their migration into tissue sites. The primary reason for our study was to determine if such in vitro-converted Tregs could be used in vivo to influence the outcome of a virus-induced immunoinflammatory lesion in the eye caused by herpes simplex virus infection. We could show in three separate models of herpetic stromal keratitis that adoptive transfers of in vitro-converted Tregs effectively diminished lesion severity, especially when given in the initial phases of infection. The suppression effect in vivo appeared to be polyspecific. The protocol we have developed could provide a useful additional approach to control virus-induced inflammatory disease.}, number={14}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Sehrawat, Sharvan and Suvas, Susmit and Sarangi, Pranita P. and Suryawanshi, Amol and Rouse, Barry T.}, year={2008}, month={Jul}, pages={6838–6851} }