Tumor-sensitized, Vβ spectratype-selected CD8+ T cells promote graft-versus-leukemia responses in the absence of severe lethal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. (145.20)

Abstract

Abstract The successful use of allogeneic blood and marrow transplantation (BMT) in the treatment of hematological malignancies is hampered by the fact that many donor T cells responsible for mediating graft-versus-leukemia (GVL) effects are also involved in development of graft-versus-host disease (GVHD). Optimizing outcomes for allo-BMT depends upon successful separation of GVHD and GVL responses. Our work focuses on identifying host reactive and tumor reactive T cells based on TCR Vβ CDR3-size spectratype analysis. In this study, we used a MHC-matched, miHA-mismatched murine model of BMT (B10.BR→CBA) and a CBA-derived myeloid leukemia, MMC6. Previous studies have shown this GVHD model to be mediated by CD4+-independent CD8+ T cells. Here, we show that the Vβ13 family is uniquely skewed in the B10.BR anti-MMC6 CD8+ T cell response. Transplantation of CD8+Vβ13+ T cells at the dose equivalent of 10x106 CD8+ T cells, the dose at which recipient mice develop severe lethal GVHD, did not mediate GVHD or GVL. Increased doses of Vβ13+ T cells led to increased GVL responses, however, recipient mice began to exhibit symptoms of GVHD. Of most interest, when recipients were given MMC6 presensitized Vβ13+ donor T cells, they displayed a significant GVL response in the absence of lethal GVHD. These results indicate that Vβ spectratyping can be used to identify T cells uniquely skewed in GVL responses and suggest that tumor-presensitized T cells can promote GVL in the absence of GVHD.