Following transplantation, acute rejection is recognized as the most frequent serious complication and the best predictor of chronic rejection, a major cause of long term graft loss. T cells are essential for initiating and maintaining acute rejection. Early intervention in transplant rejection necessitates understanding the mechanisms of T cell activation, as related to allograft survival. The principal investigator and others have found that blockade of CD40 signals prolongs graft survival. The goal of this proposal is to determine which CD40 regulated functions mediate graft rejection. CD40 signals are transduced by both NF-kB-dependent and -independent mechanisms. The PI has found that in vivo inhibition of NF-kB activation with a dominant negative transgene or by deletion of c-Rel prolongs allograft survival. Thus, one focus will be on the role of CD40-regulated actions that are NF-kB-dependent. The investigators propose the hypothesis that blockade of the CD40/CD40L costimulatory pathway prolongs allograft survival by NF-kB-dependent mechanisms. To test this hypothesis, they will employ an adoptive transfer model of cardiac transplantation using double transgenic lines that express the DO11 TCR transgene, which is cross-reactive with I-Ab, plus null alleles of either CD40, CD40L, c-Rel, or IkBa (DN), a dominant negative inhibitor of NF-kB. Transfer of cells from these animals into Balb/c recipients of C57Bl6 cardiac grafts will provide a means to examine in vivo and in vitro the molecular mechanisms governing CD40/CD40L costimulatory effects.
Aim 1 will determine the role of CD40 ligand signals on T cell activation, proliferation, unresponsiveness, and cytokine secretion.
Aim 2 will determine the cellular mechanisms by which CD40 expressed on T cells regulates allograft rejection by mechanisms of activation and apoptosis involving FasL and TNF-a signals.
Aim 3 will investigate the molecular mechanisms by which activation of NFkB controls allograft survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044085-02
Application #
6137277
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
2
Fiscal Year
2000
Total Cost
$253,020
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Liang, Yurong; Christopher, Kenneth; Finn, Patricia W et al. (2007) Graft produced interleukin-6 functions as a danger signal and promotes rejection after transplantation. Transplantation 84:771-7
DeFina, Rachel A; Liang, Yurong; He, Hongzhen et al. (2004) Analysis of immunoglobulin and T-cell receptor gene deficiency in graft rejection by gene expression profiles. Transplantation 77:580-6
Christopher, Kenneth; Liang, Yurong; Mueller, Thomas F et al. (2004) Analysis of the major histocompatibility complex in graft rejection revisited by gene expression profiles. Transplantation 78:788-98
Christopher, K; Mueller, T F; Liang, Y et al. (2004) Modulation of gene expression by alloimmune networks following murine heart transplantation. Mol Genet Genomics 271:687-96
Liang, Yurong; Christopher, Kenneth; DeFina, Rachel et al. (2003) Analysis of cytokine functions in graft rejection by gene expression profiles. Transplantation 76:1749-58
DeFina, Rachel; Christopher, Kenneth; He, Hongzhen et al. (2003) Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles. J Mol Med 81:655-63
Christopher, Kenneth; Mueller, Thomas F; DeFina, Rachel et al. (2003) The graft response to transplantation: a gene expression profile analysis. Physiol Genomics 15:52-64
Mueller, Thomas F; Ma, Chunyan; Lederer, James A et al. (2003) Differentiation of stress, metabolism, communication, and defense responses following transplantation. J Leukoc Biol 73:379-90
McKee, Charlotte M; Defina, Rachel; He, Hongzhen et al. (2002) Prolonged allograft survival in TNF receptor 1-deficient recipients is due to immunoregulatory effects, not to inhibition of direct antigraft cytotoxicity. J Immunol 168:483-9
Christopher, Kenneth; Mueller, Thomas F; Ma, Chunyan et al. (2002) Analysis of the innate and adaptive phases of allograft rejection by cluster analysis of transcriptional profiles. J Immunol 169:522-30

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