Despite advances in invasive and non-invasive therapeutic strategies, cardiac transplantation remains the final treatment option for several cardiovascular pathologies. Although acute and chronic graft rejection, involve a repertoire of humoral and cellular immunological responses, a predominant goal in the transplantation community is the prevention of T cell-mediated acute rejection. Current treatments aim at suppression or blockade of interferon (IFN)-v produced by effector T cells which ultimately lead to activation of the other arms of the immune response and subsequent rejection of the grafted organ. Recent work in our laboratory indicates that the chemokine CXCL9/Monokine Induced by IFN-? (MIG) plays a role in the polarization of effector CD4 and CD8 T cells to an IFN-?-producing phenotype. I hypothesize that, following vascularized cardiac allografting, MIG production in the spleen is correlated with upregulation of CXCR3 on T cells during priming, and that the timing is appropriate to drive naive T cells to an IFN-v-producing effector phenotype. Additionally, I believe that MIG is not a crucial or determinate factor in promoting effector infiltration into the graft despite expression of CXCR3 on CD8 and CD4 T cells. This proposal outlines the methods I will use to test how MIG production at the site of alloreactive T cell priming correlates to the differentiation of naive T cells resulting in a predominantly IFN-v-producing phenotype.
Specific Aim 1 will test the source and temporal production of MIG at the site of priming as it correlates to T cell proliferation and generation of effector phenotype.
Specific Aim 2 will directly test the requirement for MIG to drive effector cell infiltration into allografts, and whether infiltrating effectors must express CXCR3. A more complete understanding of how T cells develop to an IFN-v-producing phenotype following exposure to alloantigen and how they migrate to a transplanted solid organ will aid in generating more appropriate and more effective targets for therapeutic intervention in the race to prevent graft rejection. ? ? ?
| Nozaki, T; Rosenblum, J M; Schenk, A D et al. (2009) CCR5 is required for regulation of alloreactive T-cell responses to single class II MHC-mismatched murine cardiac grafts. Am J Transplant 9:2251-61 |
