Ever since Owen and Medawar, transplanters have dreamed of harnessing the power of neonatally-acquired tolerance. A recent collaborative retrospective study of 198 sibling LRD renal transplant (RTX) recipients at 9 transplant centers in the US and the Netherlands has revealed a powerful beneficial influence of neonatal exposure to HLA non-inherited maternal antigens (NIMA) on survival of 1 HLA haplotype-matched living donor renal allografts. The 10 year graft survival of NIMA-HLA mismatched haploidentical sibling RTX was equivalent to that of HLA-identical siblings. Paradoxically, the beneficial effect of NIMA versus NIPA mismatch was seen despite a significant (p less than .05) tendency toward earlier and greater cumulative incidence of first rejection episodes in the former. We hypothesize that the beneficial NIMA effect involves three separate components: 1) tolerization of allospecific B cells by soluble maternal HLA-NIMA present in placental blood and in milk, 2) tolerization of """"""""indirect pathway"""""""" T helper cells by soluble maternal HLA-NIMA reprocessed and presented as peptides by immature APC of the neonate, and 3) immunization of """"""""direct pathway"""""""" allospecific T cells and a subset of """"""""indirect pathway"""""""" T cells by cell membrane-bound and soluble NIMA-HLA presented by mature APC of the mother. To test the role of soluble vs. cell-bound MHC class I antigens in the phenomenon of non-inherited maternal antigen (NIMA)-induced tolerance we will: 1) analyse the biochemical forms of NIMA HLA proteins that contact the developing immune system, and compare the direct and indirect pathway T cell responses to these forms in normal adults; 2) determine the in vivo and in vitro correlates of the difference in NIMA vs. NIPA-mismatched sibling renal allograft survival; and 3) analyze the mechanism of the NIMA transplant tolerance effect in a mouse vascularized allograft model. Our goal is to establish the basis for a rational approach to HLA-matching and selective NIMA mismatching to achieve the goal of clinical kidney transplantation tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044077-03
Application #
6349874
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Prasad, Shiv A
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$207,490
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
Burlingham, William J; Jankowska-Gan, Ewa; Kempton, Steve et al. (2015) Patterns of Immune Regulation in Rhesus Macaque and Human Families. Transplant Direct 1:e20
Burlingham, William J; Goulmy, Els (2008) Human CD8+ T-regulatory cells with low-avidity T-cell receptor specific for minor histocompatibility antigens. Hum Immunol 69:728-31
Torrealba, Jose R; Katayama, Masaaki; Fechner Jr, John H et al. (2004) Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1+CD4+ T regulatory cell infiltrates. J Immunol 172:5753-64
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
Rodriguez, Daniel S; Jankowska-Gan, Ewa; Haynes, Lynn D et al. (2004) Immune regulation and graft survival in kidney transplant recipients are both enhanced by human leukocyte antigen matching. Am J Transplant 4:537-43
Molitor, Melanie L; Haynes, Lynn D; Jankowska-Gan, Ewa et al. (2004) HLA class I noninherited maternal antigens in cord blood and breast milk. Hum Immunol 65:231-9
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

Showing the most recent 10 out of 12 publications