Achieving long-term allograft survival in the absence of ongoing immunosuppressive treatment is an important goal in clinical organ transplantation. Homeostatic mechanisms that regulate T-lymphocyte survival during alloimmune responses are probably central to determining the fate of a transplanted organ. There is evidence to show that T-lymphocytes are susceptible to activation-induced apoptotic death following exposure to high antigen dose or persistent antigenic stimulation. The extent to which activation-induced T-cell death contributes to long-term allograft survival and transplantation tolerance is not known. The underlying thesis in this proposal is that activation-induced death of alloreactive T-cells is necessary but not sufficient for induction of long-term allograft survival and transplantation tolerance; suppression of factors that rescue T-cells from death is required to achieve these outcomes.
Specific aim 1 is to study the role of activation-induced T-cell death in the induction of long-term allograft survival and transplantation tolerance to vascularized allografts. Heart transplant acceptance will be examined in gene-knockout mice deficient in membrane molecules or cytokines that mediate activation-induced cell death. Biochemical, histochemical, and flow cytometric techniques will be used to study apoptosis of alloreactive T-cells in vivo and in vitro.
Specific aim 2 is to study the role of activated antigen presenting cells in rescuing T-lymphocytes from cell death, thus precluding long term-allograft survival and transplantation tolerance. In vivo and in vitro systems will be used to determine which antigen presenting cell cytokines or membrane molecules can rescue activated, alloreactive T-lymphocytes from apoptosis. An in vivo system consisting of scid mice transfused with T-cell receptor-transgenic lymphocytes will be utilized to study intragraft factors that prevent activation-induced T-cell death. The proposed studies will enhance our understanding of T-cell survival following allostimulation and refine our abilities to design and implement new therapies that induce tolerance to transplanted organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI041643-01
Application #
2386074
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-06-01
Project End
2002-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Dai, Z; Lakkis, F G (1999) The role of cytokines, CTLA-4 and costimulation in transplant tolerance and rejection. Curr Opin Immunol 11:504-8

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