Mechanisms underlying the complex interrelationships of infection and graft survival during induction and maintenance of transplantation tolerance are not well understood. Our goal is to understand how infection blocks the induction of peripheral and central tolerance. We have developed several innovative technologies for identifying virus-immune T cells and determining their anti-viral and cross-reactive alloreactivity at the single cell level. We have also developed methods for 1) quantifying alloreactive T cells using a 'synchimera'model based on CD8+ TCR Tg mice, 2) identifying naive and effector alloreactive T cells by their rapid production of cytokines following alloantigen stimulation, and 3) quantifying in vivo CDS T cell effector function using an in vivo cytotoxicity assay. We will use these techniques with an exciting new technology for in vivo delivery of siRNA to block of CD40-CD154 interaction. These new technologies will allow us to test our overall hypothesis that induction of pro-inflammatory cytokines and IFN1 is a fundamental mechanism by which innate immune activation modulates the induction of peripheral and central tolerance.
Specific Aim 1 is to determine mechanisms by which TLR ligation or virus infection modulates the induction of peripheral tolerance. We will test the hypothesis that innate immune activation by TLR agonists or virus infection abrogates the induction of peripheral tolerance through the production of pro-inflammatory cytokines and IFN1.
Specific Aim 2 is to determine mechanisms by which TLR ligation or virus infection modulates establishment of hematopoietic chimerism and central tolerance. We will test the hypothesis that the induction of peripheral and central tolerance involves multiple different but overlapping mechanisms. This project should reveal the mechanism(s) by which infection compromises the induction of peripheral and central transplantation tolerance. This Project will interact closely with Project 2 studying the maintenance of tolerance, and Project 3 studying how alloreactive CD8 T cells die by apoptosis following costimulation blockade. These discoveries will be translated to human immune systems in Project 4 using both the Viral and Technology Core and Animal Core as critical resources for the accomplishment of our research goals.
As new drugs for prolonging graft survival in pafients are implemented in the clinic, the safety and efficacy of these new drugs in the face of environmental insults such as infections are not known. This work will identify how infection during transplantafion may affect the host immune system and ultimate fate of the graft.
|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|
Showing the most recent 10 out of 112 publications