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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
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
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 β 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