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.