Sensitization or antibody production to alloantigens present in blood transfusions and organ allografts precludes transplantation of as many as 25% of potential kidney graft recipients. Our objective is to develop a rational approach to specific desensitization of HLA class I-sensitized patients by means of antigen receptor-specific reagents. Our approach is based, in part, on our preliminary data supporting the hypothesis that human B cell responses to HLA class I are directed to relatively few polymorphic epitopes and are idiotypically restricted in both the 10 (IgM) and 20 (IgG) response repertoire. The rationale for the project is that by developing anti-idiotypic (Ab-2) reagentS specific for the restricted VH- and VL-encoded idiotopes on anti-HLA class I B cells, as well as soluble divalent and decavalent forms of HLA class I recombinant fusion proteins, specific therapy to eliminate these B cells can be developed. The specific alms are: l) to further characterize the human B cell response to HLA-A2 at both protein (epitope and idiotype) and DNA (V region gene utilization) levels with the goal of identifying new targets for receptor-based therapy; 2) to develop and test monoclonal and polyclonal Ab-2 reagents as immunotoxins in the hu/SCID in vivo model system for anti-HLA-A2 response developed in our laboratory. In addition to developing and testing new Ab-2 reagents and immunotoxins, we propose to test a novel class of HLA class I/Ig fusion proteins that resemble anti-idiotype in terms of valency and ability to specifically bind to B cells bearing receptors for HLA-A2; and 3) to use the hu/SCID model to evaluate the role of HLA-A2 peptide-specific T helper (TH) cells in the generation of antibody responses to HLA-A2 and to determine the cell subsets required to induce Tn-dependent B primary and memory cell IgG responses in vivo. The possible therapeutic effectiveness of TH cell inhibition (e.g., anti-CD4 mAb, high dose peptide) will be evaluated using the hu/SCID model. The three parts of the project form an integrated approach to analysis of the processes of sensitization and de-sensitization to MHC class I alloantigens, with an emphasis on identifying the cells and molecules involved in both. The overall goal is to develop an effective therapy to reverse the sensitized state, and prevent its re-emergence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI026941-06A2
Application #
2063662
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1989-04-01
Project End
1998-06-14
Budget Start
1995-06-15
Budget End
1996-06-14
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Demaria, S; DeVito-Haynes, L D; Salter, R D et al. (1999) Peptide-conformed beta2m-free class I heavy chains are intermediates in generation of soluble HLA by the membrane-bound metalloproteinase. Hum Immunol 60:1216-26
Burlingham, W J; Jankowska-Gan, E; DeVito-Haynes, L et al. (1998) HLA (A*0201) mimicry by anti-idiotypic monoclonal antibodies. J Immunol 161:6705-14
DeVito-Haynes, L D; Demaria, S; Bushkin, Y et al. (1998) The metalloproteinase-mediated pathway is essential for generation of soluble HLA class I proteins by activated cells in vitro: proposed mechanism for soluble HLA release in transplant rejection. Hum Immunol 59:426-34
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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

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