Solid organ transplantation remains the final common pathway for many end-stage diseases. However, mandatory non-specific immunosuppresion and acute rejection continue to result in significant morbidity and mortality. Our lab has thus far demonstrated that the CD4 T-cell is necessary and sufficient alone to illicit acute cardiac rejection. Additionally, we have shown that the 'direct' (donor-restricted) pathway is necessary for acute rejection whereas the 'indirect' (host-restricted) is not. A question that remains is which cell type is responsible for antigen presentation in 'direct' CD4-mediated acute cardiac rejection. We propose to answer this question by isolating antigen presentation to endothelial cells/cardiomyocytes or to dendritic cells by using bone marrow transplantation to create chimeric mice. As CD4-mediated rejection is is restricted by MHC class II expression, MHC class II knockout mice can be used as bone marrow recipients or donors, allowing isolation of MHC class II expression to the bone marrow-derived compartment or to the tissue-derived compartment (eg. endothelial cells). These chimeric mice can then serve as heart donors into immunodeficient recipients reconstituted with CD4 T-cells. Results of these studies will have significant implications for targeted therapy.
| Grazia, Todd J; Pietra, Biagio A; Johnson, Zachary A et al. (2004) A two-step model of acute CD4 T-cell mediated cardiac allograft rejection. J Immunol 172:7451-8 |
