? Failure to stem the incidence of chronic rejection continues to diminish the long-term benefits of transplantation. Experimental data suggest the importance of tolerance induction as a means to prevent chronic rejection and minimize drug toxicity, and blockade of CD28/B7 and/or CD154/CD40 can markedly prolong allograft survival, in some cases leading to permanent engraftment. However, costimulation blockade-resistant allograft rejection can still occur. This application is based around recently recognized CD28 and B7 homologs whose ligands are broadly expressed in peripheral tissues, and which likely regulate effector T and B cell responses. We will study the roles of ICOS/B7RP-1 and PD-1/PD-L1/PD-L2 in host alloresponses using murine models of cardiac and islet allograft rejection, thereby allowing consideration of rejection in primarily revascularized vs. non-revascularized grafts, as well as validation of heterotopic cardiac graft data in the more stringent, life-supporting islet allograft system.
Aim 1 will determine the mechanisms by which the ICOS/B7RP-1 costimulatory pathway can regulate T and B cells responses in allograft recipients in vivo, such that targeting of this interaction can diminish chronic rejection and promote tolerance induction. We will dissect the contributions of ICOS and B7RP-1 to T and B cell responses in wild-type as well as CD28- and CD154-independent responses. We anticipate these studies will provide key mechanistic insights into the importance of ICOS/B7RP-1 in ongoing host alloresponses, and how targeting of this pathway can best promote allograft tolerance.
Aim 2 hypothesizes that tissue-specific immune responses are regulated by the PD-1/PD-L1/PD-L2 pathway, and we propose to analyze the extent to which manipulation of this pathway can facilitate long-term allograft survival. Our preliminary data show that stimulation of a negative signal through ligation of PD-1 can dampen host alloresponses, including those underlying costimulation blockade-resistant allograft rejection. We will expand these studies to dissect how interactions of PD-1 with its ligands can be promoted to achieve therapeutic effects in allograft recipients. Success in this work would provide a rationale for testing in non-human primates, and may ultimately improve the management and long-term results seen in patients undergoing organ transplantation or receiving islet allografts by promoting graft tolerance and decreasing the incidence of chronic rejection. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054720-03
Application #
6845283
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
2003-02-15
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
3
Fiscal Year
2005
Total Cost
$425,000
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Harmon, William; Meyers, Kevin; Ingelfinger, Julie et al. (2006) Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol 17:1735-45

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