Abstract

Our objectives in this renewal application are to bring the insights gained over the past eight years of studying the donor-specific transfusion (DST) mechanisms to bear on the clinical problem of kidney allograft loss due to chronic rejection > 2 yr post-transplant. These insights include: a) the prevention of sensitization via development of anti-idiotypic network response to DST: b) the prevention of early (< 6 mo post-transplant) acute rejection coincident with the development of donor-specific hyporesponsiveness of cytotoxic T lymphocytes; c) susceptibility of HLA mismatched transplants to late graft loss > 2 years post-transplant due to chronic rejection; and d) the resistance of liver transplants to the development of late chronic rejection that affects other organ allografts. The project is divided into four parts: 1) we will utilize purified HLA class I and purified anti-HLA class I antibodies to analyze the role of T-helper and B cell subsets (IgM and IgG) in the development of anti-class I and anti-idiotypic responses; 2) we will analyze the mechanism of donor-specific CTL hyporesponsiveness by comparing CD4+ T-helper and CD8+/cytotoxic-suppressor cell function in bulk culture and in limiting dilution analysis of PBL; 3) we will compare the production of Ab-I (anti-HLA class I), Ab-2, and corresponding TH and B cell responses between liver and kidney transplant recipients, paying particular attention to the correlation with soluble class I levels in the serum; and 4) to determine if a continuous source of soluble HLA class I can inhibit primed T-helper and B cell responses, we will reconstitute scid mice with PBL from highly sensitized patients, and subject them to treatment with recombinant soluble HLA class I to determine the effect on human skin allograft rejection and anti-HLA IgG response. The information generated by all four sections of this project will be used to develop new strategies for graft prolongation using donor-specific antigen manipulation of the host.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031774-11
Application #
3230319
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1983-01-01
Project End
1994-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Kusaka, S; Grailer, A P; Fechner Jr, J H et al. (1995) Evidence for a possible Th2 bias in human renal transplant tolerance. Transplant Proc 27:225-6
Burlingham, W J; Grailer, A P; Fechner Jr, J H et al. (1995) Microchimerism linked to cytotoxic T lymphocyte functional unresponsiveness (clonal anergy) in a tolerant renal transplant recipient. Transplantation 59:1147-55
DeVito-Haynes, L D; Jankowska-Gan, E; Sollinger, H W et al. (1994) Monitoring of kidney and simultaneous pancreas-kidney transplantation rejection by release of donor-specific, soluble HLA class I. Hum Immunol 40:191-201
Geissler, E K; Wang, J; Fechner Jr, J H et al. (1994) Immunity to MHC class I antigen after direct DNA transfer into skeletal muscle. J Immunol 152:413-21
DeVito, L D; Hogan, K T; Mason, B P et al. (1993) Epitope fine specificity of human anti-HLA-A2 antibodies. Transplant Proc 25:189-90
Niguma, T; DeVito, L D; Grailer, A P et al. (1993) HLA-A2-specific antibody production in severe combined immunodeficient mice reconstituted with human peripheral blood leukocytes from HLA-presensitized donors. Transplant Proc 25:239-40
De Vito, L D; Mason, B P; Jankowska-Gan, E et al. (1993) Epitope fine specificity of human anti-HLA-A2 antibodies. Identification of four epitopes including a haptenlike epitope on HLA-A2 at lysine 127. Hum Immunol 37:165-77
Niguma, T; DeVito, L D; Grailer, A P et al. (1993) Activation of HLA-A2-specific memory B cells in severe combined immunodeficient mice. Hum Immunol 37:7-16
Burlingham, W J; Fechner, J H; DeVito, L D et al. (1993) Human interleukin-2 and lymphoproliferative (T-helper cell) responses to soluble HLA class I antigens in vitro: I. Specificity for polymorphic domains. Tissue Antigens 42:35-8
Kawamura, T; Niguma, T; Fechner Jr, J H et al. (1992) Chronic human skin graft rejection in severe combined immunodeficient mice engrafted with human PBL from an HLA-presensitized donor. Transplantation 53:659-65

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