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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046629-13
Application #
8473766
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$287,933
Indirect Cost
$102,094
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Negrin, Kimberly A; Roth Flach, Rachel J; DiStefano, Marina T et al. (2014) IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One 9:e107265
Brehm, Michael A; Wiles, Michael V; Greiner, Dale L et al. (2014) Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods 410:3-17
Amano, Shinya U; Cohen, Jessica L; Vangala, Pranitha et al. (2014) Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19:162-71
Daniels, Keith A; Hatfield, Steven D; Welsh, Raymond M et al. (2014) MHC basis of T cell-dependent heterologous immunity to arenaviruses. Virology 464-465:213-7
Jurczyk, Agata; Bortell, Rita; Alonso, Laura C (2014) Human ?-cell regeneration: progress, hurdles, and controversy. Curr Opin Endocrinol Diabetes Obes 21:102-8
Aouadi, Myriam; Vangala, Pranitha; Yawe, Joseph C et al. (2014) Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance. Am J Physiol Endocrinol Metab 307:E374-83
Aryee, Ken-Edwin; Shultz, Leonard D; Brehm, Michael A (2014) Immunodeficient mouse model for human hematopoietic stem cell engraftment and immune system development. Methods Mol Biol 1185:267-78
Urban, Stina L; Welsh, Raymond M (2014) Out-of-sequence signal 3 as a mechanism for virus-induced immune suppression of CD8 T cell responses. PLoS Pathog 10:e1004357
Maykel, Justin; Liu, Jian Hua; Li, Hanchen et al. (2014) NOD-scidIl2rg (tm1Wjl) and NOD-Rag1 (null) Il2rg (tm1Wjl) : a model for stromal cell-tumor cell interaction for human colon cancer. Dig Dis Sci 59:1169-79
Sabio, Guadalupe; Davis, Roger J (2014) TNF and MAP kinase signalling pathways. Semin Immunol 26:237-45

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