title: Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vβ 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 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 × 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(+)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.
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Fanning
authors.forename: Jenny
authors.initials: J
authors.lastname: Zilberberg
authors.forename: Johann
authors.initials: J
authors.lastname: Stein
authors.forename: Kristin
authors.initials: K
authors.lastname: Vazzana
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Berger
authors.forename: Robert
authors.initials: R
authors.lastname: Korngold
authors.forename: Thea M
authors.initials: TM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D022801:Complementarity Determining Regions / Q000096:biosynthesis; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*
chemical_list: D022801:Complementarity Determining Regions; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta