To evaluate the consequences of allosensitization in transplant recipients, the inter-relationships between cellular allosensitization, humoral allosensitization, and acute graft rejection must first be defined.
Specific Aim 1 will identify the pathways of T cell sensitization that lead to allo-reactive DTH in allograft recipients. CD4plus and CD8 plus T cells from graft allosensitized normal, IFNgammaKO or IL4KO mice will be tested for their ability to mediate DTH after alloantigen presentation via autologous vs allogeneic APC. These studies are designed to test the hypothesis that allograft-induced DTH is mediated by IFNgamma but not IL4-producing CD4plus or CD8plus T cells after stimulation with donor alloantigen by either syngeneic or allogeneic APC.
Specific Aim 2 will identify the pathways of T cell sensitization that lead to donor-reactive IgG production in allograft recipients. CD4plus of CD8plus T celts from graft allosensitized normal, IFNgammaKO or IL4KO mice will be tested for the ability to promote donor-reactive IgG production when transferred into syngeneic B-SCID mice. These studies are designed to test the hypothesis that graft-induced IgG is promoted by IFNgamma or IL4 producing CD4plus T cells after stimulation with donor alloantigens via syngeneic, but not allogeneic APC.
Specific Aim 3 will determine the patterns of allosensitization which distinguish acute rejection, transplantation tolerance and chronic rejection. Alloractive DTH and alloantibody responses in cardiac allograft recipients made tolerant by immunosuppression will be evaluated. These studies are designed to test 2 hypotheses: 1) that cellular and humoral sensitization are dissociated in tolerant allograft recipients, and 2) that DTH is indicative of cellular sensitization leading to acute allograft rejection, while alloantibodies are indicative of humoral sensitization leading to chronic rejection.
Specific Aim 4 will develop methods to evaluate cellular and humoral allosensitization patterns in human transplant patients. ELISA and a novel trans vivo DTH analyses to monitor human antibody and DTH responses to TT or alloantigens will also continued to be developed, evaluated, and field tested using sera and PBMC from allosensitized and non-sensitized transplant patients. These techniques could be used to monitor patterns of allosensitization in transplant patients, with the goal of identifying patterns of allosensitization indicative of risk for post-transplant immunologic complications (acute or chronic rejection).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI040909-01
Application #
2005463
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
Dierksheide, Julie E; Baiocchi, Robert A; Ferketich, Amy K et al. (2005) IFN-gamma gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice. Blood 105:1558-65
Pelletier, Ronald P; Hennessy, Patrice K; Adams, Patrick W et al. (2002) Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney-pancreas transplantation. Am J Transplant 2:134-41
Valujskikh, A; VanBuskirk, A M; Orosz, C G et al. (2001) A role for TGFbeta and B cells in immunologic tolerance after intravenous injection of soluble antigen. Transplantation 72:685-93
VanBuskirk, A M; Malik, V; Xia, D et al. (2001) A gene polymorphism associated with posttransplant lymphoproliferative disorder. Transplant Proc 33:1834
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
Bickerstaff, A A; VanBuskirk, A M; Wakely, E et al. (2000) Transforming growth factor-beta and interleukin-10 subvert alloreactive delayed type hypersensitivity in cardiac allograft acceptor mice. Transplantation 69:1517-20
VanBuskirk, A M; Burlingham, W J; Jankowska-Gan, E et al. (2000) Human allograft acceptance is associated with immune regulation. J Clin Invest 106:145-55
Sirak, J H; Orosz, C G; Roopenian, D C et al. (1998) Cardiac allograft tolerance: failure to develop in interleukin-4-deficient mice correlates with unusual allosensitization patterns. Transplantation 65:1352-6
Orosz, C G; VanBuskirk, A M (1998) Immune mechanisms of acute rejection. Transplant Proc 30:859-61

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