Apperley

Cremer

Friedman

Hamilton

Horowitz

Jenny Zilberberg

Johann Stein

Jones

Kagamu

Kolb

Korngold

Kristin Vazzana

Leone

Marmont

Robert Korngold

Small

Stacey L. Fanning

Stephanie A. Berger

Thea M. Friedman

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 Vβ CDR3-size spectratype analysis to first show that the Vβ13 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+Vβ13+ T cells at the dose equivalent of their constituency in 1 × 107 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+Vβ13+ 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+Vβ13+ T cells accounting for the observed in vivo effects. When BMT recipients were given MMC6-presensitized CD8+Vβ13+ T cells, they displayed a significant GVL response with minimal GVHD. Spectratype analysis of tumor-presensitized, gut-infiltrating CD8+Vβ13+ T cells showed preferential usage of tumor-reactive CDR3-size lengths, and these cells expressed increased effector memory phenotype (CD44+CD62L−/lo). Thus, Vβ spectratyping can identify T cells involved in antihost and antitumor reactivity and tumor presensitization can aid in the separation of GVHD and GVL responses.</jats:p

Crossref

The Journal of Immunology

Unraveling Graft-versus-Host Disease and Graft-versus-Leukemia Responses Using TCR Vβ Spectratype Analysis in a Murine Bone Marrow Transplantation Model

Unraveling Graft-versus-Host Disease and Graft-versus-Leukemia Responses Using TCR Vβ Spectratype Analysis in a Murine Bone Marrow Transplantation Model

Abstract

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