Long-term allograft survival is readily achieved in murine cardiac allograft recipients, but very little is known about the mechanisms by which this allograft acceptance is induced or maintained. We have developed a testable, working paradigm of cardiac allograft acceptance. This paradigm holds that allograft acceptance involves immune processes that actively protect allografts. We believe that one manifestation of this alloprotective process, the phenomenon of linked antigen non-responsiveness, holds the key to understanding allograft acceptance. The proposed studies will investigate important aspects of the alloprotective responses that develop in allograft recipients.
Specific Aim 1 : To evaluate the contributions of three intriguing cell types to the initiation of allograft acceptance responses. These are addressed as the """"""""memory hypothesis"""""""", the """"""""gamma/delta hypothesis"""""""", and the """"""""NKT hypothesis"""""""". In general, we will use cell transfer studies with SCID mice to determine the role of memory T cells, gammadeltaT cells or NKT cells in the generation of alloprotective activity, ie., linked DTH non-responsiveness or cardiac allograft acceptance.
Specific Aim 2 : To evaluate two non-competing mechanisms by which allograft acceptance is maintained. These are addressed as the """"""""cytokine synergy hypothesis"""""""" and the """"""""protected compartment hypothesis"""""""". In general, we will use cytokine knock-out mice and anti-cytokine antibodies to dissect the roles of TGFbeta, IL10 and IL4 in the expression of alloprotective activity (linked DTH non-responsiveness and cardiac allograft acceptance). We will also determine whether new alloprotective mechanisms independent of these cytokines are installed in accepted allografts over time.
Specific Aim 3 : To identify the cytokine environment necessary for the in vitro generation of alloprotective T cells that can be transferred into allograft recipients to promote cardiac allograft acceptance. Initially, these studies will use IL10 to drive alloantigen- stimulated splenic T cells towards alloprotective behavior.
Specific Aim 4 : To evaluate and optimize the experimental system in which tolerization to BSA, a foreign protein unrelated to an allograft, can be used to promote linked non-responsiveness to graft alloantigens, and thus educate an allograft recipient toward allograft acceptance. This represents a novel therapeutic approach that uses BSA as a """"""""vaccine"""""""" for transplant recipients. Routine molecular genetic methods would allow us to explore the potential of this vaccine strategy for use as a potential gene therapy in transplant recipients. Finally, we will evaluate the effects of concurrent infection with murine influenza virus on he survival of the graft and recipient in mice that are being educated with BSA for allograft acceptance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061966-04
Application #
6490634
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Massicot-Fisher, Judith
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2003-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$290,687
Indirect Cost
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Pelletier, Ronald P; Bickerstaff, Alice A; Adams, Patrick W et al. (2007) Evaluation of immune regulation in transplant patients using the trans vivo delayed type hypersensitivity assay. Hum Immunol 68:514-22
Bickerstaff, Alice A; Wang, Jiao-Jing; Xia, Dongyuan et al. (2002) Allograft acceptance despite differential strain-specific induction of TGF-beta/IL-10-mediated immunoregulation. Am J Transplant 2:819-27
Bickerstaff, Alice; Orosz, Charles (2002) Evidence for a limited contribution of immune regulation to cardiac allograft acceptance. Hum Immunol 63:935-47
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
Pelletier, Ronald P; Hennessy, Patrice K; Adams, Patrick W et al. (2002) High incidence of donor-reactive delayed-type hypersensitivity reactivity in transplant patients. Am J Transplant 2:926-33
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
Bishop, D K; Chan Wood, S; Eichwald, E J et al. (2001) Immunobiology of allograft rejection in the absence of IFN-gamma: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions. J Immunol 166:3248-55
Xia, D; Sanders, A; Shah, M et al. (2001) Real-time polymerase chain reaction analysis reveals an evolution of cytokine mRNA production in allograft acceptor mice. Transplantation 72:907-14
Bickerstaff, A A; Wang, J J; Pelletier, R P et al. (2001) Murine renal allografts: spontaneous acceptance is associated with regulated T cell-mediated immunity. J Immunol 167:4821-7
Waldman, W J; Bickerstaff, A; Gordillo, G et al. (2001) Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide. Transplantation 72:1578-82

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