The overall goal of this research program is to understand transplantation tolerance mediated by costimulation blockade. This form of transplantation tolerance is associated with the deletion of alloreactive CDS T cells. Importantly, the activation of innate immunity by virus infection or exposure to Toll-like receptor agonists can prevent both alloreactive CDS T cell deletion and tolerance induction. The specific focus of this Study is to define the molecular mechanisms of CDS T cell apoptosis. We propose to examine the biochemical mechanism of CDS T cell death (Specific Aim 1). These Studies will provide the foundation for molecular studies of specific pathways of CD8 T cell death (Specific Aims 2 &3). It is established that members of the Bcl2 protein family act as critical regulators of CDS T cell death. Moreover, members ofthe stress-activated protein kinase family are implicated in the regulation of CDS T cell death. We will examine these pathways during the induction of transplantation tolerance during co-stimulation blockade. We will also examine CDB T cell death when transplantation tolerance is disrupted by exposure to Toll-like receptor agonists and lymphocytic choriomeningitis virus (LCMV) infection. These studies are fully integrated within the theme of the Program Project and depend upon collaborative studies with the other Projects.
The Specific Aims of this proposal are to examine the: 1. Biochemical mechanism of CDS T cell death. 2. Role of stress-activated MAP kinases in CDS T cell death. 3. Role of Bcl2 family proteins in CDB T cell death. We anticipate that the successful completion of these studies will provide important new insight into the understanding of transplantation tolerance and that the new information we obtain will contribute to the design of therapies for the treatment of human disease.
The induction of immune tolerance is important for successful organ transplantation. The focus of this Program Project is the analysis of a co-stimulation blockade protocol that leads to the deletion of alloreactive CDS T cells. The goal of this project is to define the biochemical mechanism of CDB T cell death. This information is critical for understanding immune tolerance and for the development of improved therapeutic strategies.
|Watkin, Levi B; Mishra, Rabinarayan; Gil, Anna et al. (2017) Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. J Allergy Clin Immunol 140:1206-1210|
|Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2017) Heterologous Immunity and Persistent Murine Cytomegalovirus Infection. J Virol 91:|
|Aslan, Nuray; Watkin, Levi B; Gil, Anna et al. (2017) Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires. MBio 8:|
|Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9|
|Hasgur, Suheyla; Aryee, Ken Edwin; Shultz, Leonard D et al. (2016) Generation of Immunodeficient Mice Bearing Human Immune Systems by the Engraftment of Hematopoietic Stem Cells. Methods Mol Biol 1438:67-78|
|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|
|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 138:769-779|
|Cohen, Jessica L; Shen, Yuefei; Aouadi, Myriam et al. (2016) Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA. Mol Pharm 13:964-978|
|Tencerova, Michaela; Aouadi, Myriam; Vangala, Pranitha et al. (2015) Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB J 29:2959-69|
|Gil, Anna; Yassai, Maryam B; Naumov, Yuri N et al. (2015) Narrowing of human influenza A virus-specific T cell receptor ? and ? repertoires with increasing age. J Virol 89:4102-16|
Showing the most recent 10 out of 118 publications