HLA -A, and -B class I proteins are cell-surface-expressed peptide- binding proteins responsible for immune control of viral infections in human tissues, and for immune surveillance of certain types of cancers. They are also powerful stimulators of allospecific antibody responses in mammalian pregnancy and in recipients of HLA-A, -B mismatched organ and tissue transplants. HLA-A, -B antigens and associated 'minor H' antigenic peptides, when expressed on costimulatory donor antigen-presenting cells, can activate specific CD8 + precursor T cells for recruitment to the graft from the lymph nodes and spleen via the blood. There the A,B antigens, expressed on virtually all cell types, can serve as targets for the diffuse tissue infiltration and damage commonly found in episodes of acute cellular rejection. However, little is known about the precise role of the donor HLA-A, -B antigens in the graft-host relationship that develops during chronic rejection, particularly in light of the focal nature of the infiltrates, the bias toward CD4+ T cells in perivascular lesions, the importance of humoral antibody in some cases, and in most cases, the absence of interstitial inflammation characteristic of acute rejection. This proposal will test a hypothesis that the local and systemic release of soluble forms of donor-cell-derived HLA-A, -B antigens stimulates a host CD4+ T cell response to reprocessed HLA-A, -B alloantigen, that is the principal driving force for eventual humoral and cell-mediated chronic rejection of organ transplantation. This award will enhance my career development by allowing me to devote my primary research effort to new basic science approaches to the related problems of HLA class i-specific acute and chronic rejection in clinical transplantation. It will also provide entry into a new area of research, namely the use of a DNA vaccine approach for analysis of in vitro and in vivo immune response to reprocessed HLA-class I allo(peptide) antigen, which will directly compliment my previous training in mouse skin transplantation and enhance my career interest in learning new ways of preventing HLA-class I-specific sensitization and inducing HLA-class I-specific tolerance in human clinical organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AI001452-04
Application #
6169199
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
2000
Total Cost
$107,325
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
Xu, Qingyong; Lee, Junglim; Keller, Melissa et al. (2009) Analysis of indirect pathway CD4+ T cells in a patient with metastable tolerance to a kidney allograft: possible relevance to superior graft survival of HLA class II closely matched renal allografts. Transpl Immunol 20:203-8
Xu, Qingyong; Lee, Junglim; Jankowska-Gan, Ewa et al. (2007) Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. J Immunol 178:3983-95
Cai, Junchao; Lee, Junglim; Jankowska-Gan, Ewa et al. (2004) Minor H antigen HA-1-specific regulator and effector CD8+ T cells, and HA-1 microchimerism, in allograft tolerance. J Exp Med 199:1017-23
Andrassy, Joachim; Kusaka, Satoshi; Jankowska-Gan, Ewa et al. (2003) Tolerance to noninherited maternal MHC antigens in mice. J Immunol 171:5554-61
Jankowska-Gan, Ewa; Rhein, Tonja; Haynes, Lynn D et al. (2002) Human liver allograft acceptance and the ""tolerance assay"". II. Donor HLA-A, -B but not DR antigens are able to trigger regulation of DTH. Hum Immunol 63:862-70
Geissler, F; Jankowska-Gan, E; DeVito-Haynes, L D et al. (2001) Human liver allograft acceptance and the ""tolerance assay"": in vitro anti-donor T cell assays show hyporeactivity to donor cells, but unlike DTH, fail to detect linked suppression. Transplantation 72:571-80
Burlingham, W J; Jankowska-Gan, E; VanBuskirk, A et al. (2000) Loss of tolerance to a maternal kidney transplant is selective for HLA class II: evidence from trans-vivo DTH and alloantibody analysis. Hum Immunol 61:1395-402
Kusaka, S; Grailer, A P; Fechner Jr, J H et al. (2000) Clonotype analysis of human alloreactive T cells: a novel approach to studying peripheral tolerance in a transplant recipient. J Immunol 164:2240-7
O'Connell, P J; Burlingham, W J (1999) Donor dendritic cell persistence in organ allograft recipients in the absence of immunosuppression. J Leukoc Biol 66:301-5
O'Connell, P J; Mba-Jonas, A; Leverson, G E et al. (1998) Stable lung allograft outcome correlates with the presence of intragraft donor-derived leukocytes. Transplantation 66:1167-74

Showing the most recent 10 out of 12 publications