The major complication associated with organ transplantation is allograft rejection, which is mediated by graft-reactive T cells. Rejection is controlled by non specific immunosuppressive therapies, which often lead to life threatening infections. Hence, transplant patients would benefit significantly from the development of therapies which selectively target graft.reactive T cells and induce graft-specific tolerance. It is widely accepted that CTL and DTH responses are the principle effector mechanisms of allograft rejection. Members of the beta-chemokine family of chemoattractants likely regulate graft infiltration by CLT and other leukocytes. Since CLT and DTH responses are promoted by the Th1 products IL-2 and IFN-gamma graft-reactive Th1 cells provide a target for tolerance inducing strategies. It is well documented that the Th2 products IL-4 and IL-10 inhibit Th1 development. Further, evidence suggests that Th2 cytokines influence chemokine production. Hence, an increasingly popular hypothesis states that selective induction of graft-reactive Th2 cells would promote graft.specific tolerance. By promoting an early shift from Th1 to Th2 cytokine production, acute rejection episodes, which likely contribute to chronic rejection, may be prevented. To date, this attractive hypothesis has not been rigorously tested. Since we and others have reported that Th2 cytokines may promote alternate (non Cit) mechanisms of graft rejection, it is essential to define the in vivo biologic activities of Th2 cells in the context of transplantation. We hypothesize that Th2 cells mediate both tolerogenic and deleterious activities and that these activities may be segregated for therapeutic purposes. This hypothesis will be tested in a comprehensive in vivo system which combines the mouse cardiac transplant model with modified LDA to quantify graft-reactive T cell development, RT-PCR to evaluate in situ cytokine gene expression, histologic analyses to evaluate tissue damage, and immunohistochemistry to evaluate endothelia expression of chemokines. Specifically, we will: l) Identify tolerogenic and deleterious activities of Th2 and determine if deleterious activities may be ablated leaving tolerance inducing factors intact. Graft-reactive Th2 will be generated in vitro and adoptively transferred into Thy l congenic and scid cardiac allograft recipients. The roles of eosinophils, macrophages, and alloantibody in Th2 mediated tissue damage will be assessed. 2) Determine if a Th1 to Th2 shift may be induced therapeutically. Two key regulatory cytokines will be manipulated as an inductive therapy. IL-12 will be neutralized in vivo, and intragraft expression IL-10 will be achieved by gene transfer into donor hearts. 3) Determine the role of beta-chemokines in recruitment of effector mechanisms. and determine if chemokine activity may be targeted to promote allograft tolerance. This information will be essential for the development of tolerance inducing therapies based on in vivo cytokine manipulation. It is important to note that several key observations made in this experimental mouse model have been verified in human cardiac transplant patients. Hence, we anticipate that the information gained from these studies will have direct clinical relevance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031946-03
Application #
2442501
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Welling, Theodore H; Lu, Guanyi; Csencsits, Keri et al. (2008) Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation. Surgery 143:394-403
Brown, David L; Bishop, D Keith; Wood, Sherri Y et al. (2006) Short-term anti-CD40 ligand costimulatory blockade induces tolerance to peripheral nerve allografts, resulting in improved skeletal muscle function. Plast Reconstr Surg 117:2250-8
Csencsits, K; Wood, S C; Lu, G et al. (2006) Transforming growth factor beta-induced connective tissue growth factor and chronic allograft rejection. Am J Transplant 6:959-66
Rovak, Jason M; Bishop, D Keith; Boxer, Leslie K et al. (2005) Peripheral nerve transplantation: the role of chemical acellularization in eliminating allograft antigenicity. J Reconstr Microsurg 21:207-13
Csencsits, Keri; Wood, Sherri Chan; Lu, Guanyi et al. (2005) Transforming growth factor-beta1 gene transfer is associated with the development of regulatory cells. Am J Transplant 5:2378-84
Nathan, Meera J; Mold, Jeffrey E; Wood, Sherri C et al. (2004) Requirement for donor and recipient CD40 expression in cardiac allograft rejection: induction of Th1 responses and influence of donor-derived dendritic cells. J Immunol 172:6626-33
Csencsits, Keri L; Bishop, D Keith (2003) Contrasting alloreactive CD4+ and CD8+ T cells: there's more to it than MHC restriction. Am J Transplant 3:107-15
Nathan, Meera J; Yin, Dengping; Eichwald, Ernst J et al. (2002) The immunobiology of inductive anti-CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells. Am J Transplant 2:323-32
Chan, S Y; Goodman, R E; Szmuszkovicz, J R et al. (2000) DNA-liposome versus adenoviral mediated gene transfer of transforming growth factor beta1 in vascularized cardiac allografts: differential sensitivity of CD4+ and CD8+ T cells to transforming growth factor beta1. Transplantation 70:1292-301
DeBruyne, L A; Li, K; Bishop, D K et al. (2000) Gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity. Gene Ther 7:575-82

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