Our goal is to investigate the impact of viral infection on alloreactivity on a human immune system. We will use humanized mice that develop a functional human immune system that can be infected with Epstein Barr Virus (EBV), lymphocytic choriomeningitis (LCMV), or influenza A (lAV), viruses associated with allograft rejection. In C57BL/6 mice, we have shown that heterologous immunity induced by LCMV infection leads to virus-specific allo-cross-reactive CDS T cells that can reject skin allografts and prevent tolerance induced by costimulation blockade. Ne propose to test the hypothesis in humanized mice that virus infection leads to the generation of human virus specific allo-cross-reactive T cells that participate in rejection of human allografts. Humanized mice will allow analysis of these viruses using novel technologies to quantify naive and effector human alloreactive T cells and virus-induced allo-cross-reactive T cells. These analyses will permit direct determination of their ability to participate in allograft rejection. We also propose use of innovative siRNA in vivo delivery systems to block CD40-CD154 interaction.
Aim 1 is to investigate the immune response to alloantigens in human immune system-engrafted NOD-sc/d lL2rf[null] HLA-A2 mice transplanted with human islet or skin allografts. We will quantify the alloimmune response, determine kinetics of graft infiltration and allograft rejection, and establish models for studies of virus-induced heterologous immunity on allograft survival.
Aim 2 is to quantify virus-specific and alloimmune responses during acute virus infection in humanized mice treated with costimulation blockade. We will determine human immune responses to EBV, LCMV, and lAV, and quantify virus specific and allospecific T cells that develop as a consequence of heterologous immunity. We will test the hypothesis that virus infection generates heterologous immunity by inducing the development of virus-specific allo-cross-reactive T cells that participate in allograft rejection. These unique resources, novel technologies, and combined expertise in transplantation, humanized mice, virology, and siRNA technology provide an opportunity to investigate the role of heterologous immunity induced by virus infection on alloreactivity and graft rejection in a human immune system.
|Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naÃ¯ve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9|
|Bryce, Paul J; Falahati, Rustom; Kenney, Laurie L et al. (2016) Humanized mouse model of mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. J Allergy Clin Immunol 138:769-79|
|Cohen, Jessica L; Shen, Yuefei; Aouadi, Myriam et al. (2016) Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA. Mol Pharm 13:964-78|
|Samanta, S; Sun, H; Goel, H L et al. (2016) IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35:1111-21|
|Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E et al. (2015) The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice. J Immunol 195:3011-9|
|Trabucco, Sally E; Gerstein, Rachel M; Evens, Andrew M et al. (2015) Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res 21:113-22|
|Babad, J; Mukherjee, G; Follenzi, A et al. (2015) Generation of Î² cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin Exp Immunol 179:398-413|
|Gil, Anna; Kenney, Laurie L; Mishra, Rabinarayan et al. (2015) Vaccination and heterologous immunity: educating the immune system. Trans R Soc Trop Med Hyg 109:62-9|
|Nayar, Ribhu; Schutten, Elizabeth; Jangalwe, Sonal et al. (2015) IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection. PLoS One 10:e0144826|
|Che, Jenny W; Selin, Liisa K; Welsh, Raymond M (2015) Evaluation of non-reciprocal heterologous immunity between unrelated viruses. Virology 482:89-97|
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