Vascularized organ transplants frequently develop a progressive obliterative vasculopathy, interstitial fibrosis and, in the case of kidneys, glomerulosclerosis, that lead to organ failure within a few years, in spite of continuing immunosuppressive therapy. This 'chronic rejection' process is poorly understood, and although there is clear evidence that T cell recognition of alloantigen plays a key role in initiating early acute rejection, there is little direct evidence that an active alloimmune response is responsible for progression of chronic rejection. In an established rat model of kidney and heart transplants (F344 and LEW strains) in which the sequential morphological and immunohistologic features, with associated cytokine/chemokine gene activation patterns, are well defined, the MHC antigen-driven T cell and antibody responses will be studied. These strains differ only by a class II public antigen. The hypothesis is that an ongoing alloantigen-driven response initiated by T cells primed by the indirect pathway of allorecognition is responsible for mediating the chronic rejection process. The sequences of F344 will be obtained and peptides prepared which represent the difference(s) with LEW MHC class II in order to establish the presence of T cell priming to the indirect pathway during chronic rejection. Preparation of T cell clones for transfer to naive recipients of grafts, and the use of monoclonal antibodies to TCRV/Beta families to block recognition in vivo, will test the significance of priming to immunodominant epitopes in chronic rejection. Tolerance- inducing strategies using synthetic peptides after transplantation will then be applied to interrupt the ongoing process of T cell activation. The hypothesis is supported by preliminary data showing that a single injection of CTLA4Ig to block T cell costimulation via CD28-B7, in addition to preventing chronic rejection if given early, can interrupt progression of chronic rejection when given 8 weeks after transplantation. Further study using antibodies and CTLA4Ig mutants which distinguish between B7-1 and B7-2 pathways should further elucidate approaches to interrupting chronic rejection. The synthetic MHC peptide and costimulatory blockade protocols will be tested for synergistic interaction, and full MHC class I and II strain differences will be subsequently studied. The above studies should provide relevant information for development of novel strategies to prevent and possibly interrupt chronic allograft rejection in clinical transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040629-02
Application #
2607857
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1996-12-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Yuan, Xueli; Dong, Victor M; Coito, Ana J et al. (2002) A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection. Transplantation 73:1736-42
Dong, Victor M; Yuan, Xueli; Coito, Ana J et al. (2002) Mechanisms of targeting CD28 by a signaling monoclonal antibody in acute and chronic allograft rejection. Transplantation 73:1310-7
Waaga, A M; Gasser, M; Kist-van Holthe, J E et al. (2001) Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo. J Clin Invest 107:909-16
Womer, K L; Stone, J R; Murphy, B et al. (2001) Indirect allorecognition of donor class I and II major histocompatibility complex peptides promotes the development of transplant vasculopathy. J Am Soc Nephrol 12:2500-6
Vella, J P; Magee, C; Vos, L et al. (1999) Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides. Transplantation 67:1523-32
Schaub, M; Stadlbauer, T H; Chandraker, A et al. (1998) Comparative strategies to induce long-term graft acceptance in fully allogeneic renal versus cardiac allograft models by CD28-B7 T cell costimulatory blockade: role of thymus and spleen. J Am Soc Nephrol 9:891-8
Waaga, A M; Chandraker, A; Spadafora-Ferreira, M et al. (1998) Mechanisms of indirect allorecognition: characterization of MHC class II allopeptide-specific T helper cell clones from animals undergoing acute allograft rejection. Transplantation 65:876-83
Chandraker, A; Azuma, H; Nadeau, K et al. (1998) Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection. J Clin Invest 101:2309-18
Vella, J P; Vos, L; Carpenter, C B et al. (1997) Role of indirect allorecognition in experimental late acute rejection. Transplantation 64:1823-8
Chandraker, A; Takada, M; Nadeau, K C et al. (1997) CD28-b7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury. Kidney Int 52:1678-84