Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vß spectratype analysis in a murine bone marrow transplantation model.

ABSTRACT

The optimum use of allogeneic blood and marrow transplantation (BMT) as a curative therapy for hematological malignancies lies in the successful separation of mature donor T cells that are host reactive and induce graft-versus-host disease (GVHD) from those that are tumor reactive and mediate graft-versus-leukemia (GVL) effects. To study whether this separation was possible in an MHC-matched murine BMT model (B10.BR→CBA) with a CBA-derived myeloid leukemia line, MMC6, we used TCR Vß CDR3-size spectratype analysis to first show that the Vß13 family was highly skewed in the B10.BR anti-MMC6 CD8(+) T cell response but not in the alloresponse against recipient cells alone. Transplantation of CD8(+)Vß13(+) T cells at the dose equivalent of their constituency in 1 × 10(7) CD8(+) T cells, a dose that had been shown to mediate lethal GVHD in recipient mice, induced a slight GVL response with no concomitant GVHD. Increasing doses of CD8(+)Vß13(+) T cells led to more significant GVL responses but also increased GVHD symptoms and associated mortality. Subsequent spectratype analysis of GVHD target tissues revealed involvement of gut-infiltrating CD8(+)Vß13(+) T cells accounting for the observed in vivo effects. When BMT recipients were given MMC6-presensitized CD8(+)Vß13(+) T cells, they displayed a significant GVL response with minimal GVHD. Spectratype analysis of tumor-presensitized, gut-infiltrating CD8(+)Vß13(+) T cells showed preferential usage of tumor-reactive CDR3-size lengths, and these cells expressed increased effector memory phenotype (CD44(+)CD62L(-/lo)). Thus, Vß spectratyping can identify T cells involved in antihost and antitumor reactivity and tumor presensitization can aid in the separation of GVHD and GVL responses.