Depletion of specific immunity: A novel use of recombinant MHC molecules

MHC molecules carrying selected peptides will bind specifically to their cognate T cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen specific T cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T cell populations, while leaving the remaining T cell repertoire and immune response intact, if the antigen specificity of the T cells were known. Graft-Versus-Host-Disease and other T cell mediated disorders, such as autoimmune diseases, are often the result of clonal or oligoclonal T cell expansion with reactivity against "self" proteins. Current therapies for disorders like these are often broadly immunosuppressive and leave patients at high risk for infection or relapse of malignancy.; In these studies, we successfully demonstrate that an MHC tetramer-based depletion of T cells can be achieved in a murine model of allogeneic bone marrow transplantation. Depletion of a specific alloreactive population of donor splenocytes (<0.5% of CD8+ T cells) prior to transplantation significantly decreased morbidity and mortality from Graft-Versus-Host-Disease. There was no early re-growth of the antigen-specific T cells in the recipient and in vivo CD8+ T cell proliferation was greatly reduced as well. Survival was increased greater than 3-fold over controls, yet the inherent anti-tumor activity of the transplant was retained. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T cell clones, which could result in novel therapies for certain autoimmune disorders, T cell malignancies and solid organ graft rejection.