The primary cause of late death and re-transplantation in recipients receiving organ transplant sis chronic rejection (CR). CR in the cardiac allograft is primarily manifested by loss of conduit lined by endothelial cells due to a marked migration and proliferation of smooth muscle cells into the vascular intima. Prior data from our laboratory have demonstrated that T cells from patients with CR are more allo-reactive to donor- specific vascular endothelial cells (ECs) compared to those from patients without CR, and part of this increased allo-reactivity is an increase in the expression of certain endothelial-derived mesenchymal growth factors. In the first specific aim, using a unique cell and tissue bank containing blood obtained from 75 allograft recipients serially post transplantation and matched donor-specific human aortic endothelial cells we will define the effectors responsible for inducing EC production of smooth muscle cell (SMC) growth factors (GFs). Specifically we will determine which lymphocyte subsets and which soluble (lymphokines) or membrane bound (adhesion/secondary-signal ligand pairs) cell-cell communication pathways are important in inducing EC-derived SMC GF production in these PBMC:HAEC pairs. In the second specific aim, we will define the time course of GP mRNA and protein expression in allograft vasculature in rat heterotopic heart transplants using complete MHC mismatched donors and recipients requiring chronic immunosuppression in two different strain combinations. We will correlate in vitro rat aortic endothelial cell (RAEC) GF induction by rat PBMCs (a mirror of our prior human studies) directly with in vivo GF induction in the allograft. We will define the influence of acute and """"""""subacute"""""""" parenchymal rejection and cytomegalovirus infection on GF expression and CR development in this model. We will look for evidence of chronic CMV infection in those animals infected with the virus using tissue PCR as ell as a rat CMV mutant strain expressing the beta- galactosidase genes. These studies will further delineate mechanisms of T cell-mediated growth factor regulation, correlate and confirm prior in vitro data with in vivo information and define a relevant animal model for ultimate intervention strategies.
| Raju, Raghavanpillai; Malloy, Angela; Shah, Tara et al. (2003) Alloimmune induction of endothelial cell-derived interferon-gamma-inducible chemokines. Transplantation 75:1072-4 |
| Khanna, Ashwani K; Hosenpud, Jessica S; Plummer, Matthew S et al. (2002) Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine. Transplantation 73:1543-9 |
| Hosenpud, J D; Boyle, T M; Hensler, H et al. (2000) The relationship between acute rejection and chronic rejection is highly dependent on specific MHC matching: a multi-strain rat heterotopic heart transplant study. Transplantation 69:2173-8 |
| Srivastava, R; Curtis, M; Hendrickson, S et al. (1999) Strain specific effects of cytomegalovirus on endothelial cells: implications for investigating the relationship between CMV and cardiac allograft vasculopathy. Transplantation 68:1568-73 |
