Person: Guleria, Indira
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Guleria
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Indira
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Guleria, Indira
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Publication Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity(Nature Publishing Group UK, 2018) Uehara, Mayuko; Solhjou, Zhabiz; Banouni, Naima; Kasinath, Vivek; Xiaqun, Ye; Dai, Li; Yilmam, Osman; Yilmaz, Mine; Ichimura, Takaharu; Fiorina, Paolo; Martins, Paulo N.; Ohori, Shunsuke; Guleria, Indira; Maarouf, Omar H.; Tullius, Stefan; McGrath, Martina; Abdi, RezaIschemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.Publication Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes(Public Library of Science, 2014) Kochupurakkal, Nora; Kruger, Annie J.; Tripathi, Sudipta; Zhu, Bing; Adams, La Tonya; Rainbow, Daniel B.; Rossini, Aldo; Greiner, Dale L.; Sayegh, Mohamed; Wicker, Linda S.; Guleria, IndiraAims/Hypothesis Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. Methods: Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. Results: Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. Conclusions: These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy.Publication Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells(Public Library of Science, 2015) Tripathi, Sudipta; Chabtini, Lola; Dakle, Pranal J.; Smith, Brian; Akiba, Hisaya; Yagita, Hideo; Guleria, IndiraNK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells. Specifically we observed surface receptor phenotype and cytokine production by uNK cells following TIM-3 blockade. Our results show that TIM-3 plays a role in regulating the uNK cells and contributes to the maintenance of tolerance at the feto-maternal interface.Publication Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes(American Diabetes Association, 2008) Dada, Shirine; Wong, Masie; Law, Kenneth; Wu, Erxi; Dunussi-Joannopoulos, Kyri; Bluestone, Jeffrey; Fiorina, Paolo; Vergani, Andrea; Jurewicz, Mollie; Tian, Ze; Abdi, Reza; Guleria, Indira; Rodig, Scott; Sayegh, MohamedOBJECTIVES—To investigate a B-cell–depleting strategy to reverse diabetes in naïve NOD mice. RESEARCH DESIGN AND METHODS—We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes. RESULTS—Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-cell–depleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive \(CD4^+\) T-cells into NOD.SCID hosts. CONCLUSIONS—Targeting CD22 depletes and reprograms B-cells and reverses autoimmune diabetes, thereby providing a blueprint for development of novel therapies to cure autoimmune diabetes.Publication Mechanism of EBV Inducing Anti-Tumour Immunity and Its Therapeutic Use(Springer Science and Business Media LLC, 2020-12-23) Choi, Il-Kyu; Wang, Zhe; Ke, Qiang; Hong, Min; Paul, Dereck W.; Fernandes, Stacey M.; Hu, Zhuting; Stevens, Jonathan; Guleria, Indira; Kim, Hye-Jung; Cantor, Harvey; Wucherpfennig, Kai; Brown, Jennifer R.; Ritz, Jerome; Zhang, BaochunTumour-associated antigens (TAAs) comprise a large collection of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as immunotherapy targets has been explored for over two decades, yet the genesis of TAA-specific T cells remains elusive. While tumour cells may be an important source of TAAs for T cell priming, several recent studies suggest that infection with some viruses including Epstein-Barr virus (EBV) and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs. However, the cellular and molecular basis of such responses remains undefined. Here, we show that expression of the EBV signaling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signaling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on MHC-I and -II (mainly through the endogenous pathway), and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a novel mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in patient tumour B cells and thereby empowering them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a broad array of endogenous tumour antigens, such as TAAs and neoantigens, for treating B-cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches for cancers.