Skin allografts have been used for more than 20 years as adjunctive therapy for the treatment of massive burns in humans. This approach, however, has often required immunosuppression with its inherent side effects, and has met with a limited long term success rate due to acute and chronic rejection of the allograft. The ultimate goal for the use of skin grafts in this fashion is to induce specific tolerance to the allograft, such that it is not recognized as immunologically foreign, and yet preserve an otherwise immune system. Although tolerance inducing protocols have generally met with limited success, manipulation of alloreactive T cell cytokine responses holds new promise in this area. T cell responses can be divided into two broad phenotypes based on cytokine profiles: Th1 cells predominantly produce IFNgamma and IL-2, and are postulated to mediate allograft rejection. Th2 cells predominantly produce IL-4 and IL-5, and are postulated to prevent Th1-mediated allograft rejection. Additionally, Balb/c mice (H-2d) given H-2k skin grafts have been shown to respond to a single I-Abetak peptide (I-Abetak 58-71) in the context of self-MHC. Based on these observations, we propose to induce either Th1 or Th2 responses to I-Abetak 58-71 in Balb/c mice, and determine directly whether a Th2 response can prevent allograft rejection. The strength and quality of the T cell recall responses will be determined using a ELISA spot assay. We will also test whether the induced Th1 or Th2 responses to I-Abetak 58-71 spread to other epitopes following H-2k to H-2d skin grafts. We will test for effects on the indirect pathway of allorecognition with recall response to a second known H-2d binding peptide, and will test for effects on the direct pathway of allorecognition using standard mixed lymphocyte response (MLRs). Skin graft acceptance/rejection will be used as an in vivo measure of allograft tolerance, and will be correlated with the in vitro analysis. These studies will provide answers to an important contemporary issue in alloimmune biology, that is, can manipulation of cytokine profiles prevent allograft rejection? The findings resulting from these studies may be directly applicable to human allograft transplantation.
Showing the most recent 10 out of 403 publications
