Unraveling Graft-versus-Host Disease and Graft-versus-Leukemia Responses Using TCR Vβ Spectratype Analysis in a Murine Bone Marrow Transplantation Model
| Autor: | Robert Korngold, Johann Stein, Thea M. Friedman, Stacey L. Fanning, Stephanie A. Berger, Kristin Vazzana, Jenny Zilberberg |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 190:447-457 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1201641 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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