title: Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution.
abstract: Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (T(M)) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host tissues. One approach to augmenting GVL has been to infuse ex vivo-generated T cells with defined specificities; however, this requires expertise that is not widely available. In the present study, we tested an alternative approach, adoptive immunotherapy with CD8+ T(M) from donors vaccinated against a single minor histocompatibility antigen (miHA) expressed by leukemia cells. Vaccination against the miHA H60 greatly augmented T(M)-mediated GVL against mouse chronic-phase (CP-CML) and blast crisis chronic myeloid leukemia (BC-CML). T(M)-mediated GVL was antigen specific and was optimal when H60 expression was hematopoietically restricted. Even when H60 was ubiquitous, donor H60 vaccination had a minimal impact on GVHD. T(M) from lymphocytic choriomeningitis virus (LCMV)-immune and H60-vaccinated donors augmented GVL and protected recipients from LCMV. These data establish a strategy for augmenting GVL and immune reconstitution without elaborate T-cell manipulation.
authors.affiliation: Department of Medicine, Yale University School of Medicine Cancer Center, New Haven, CT 06520-8032, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Catherine
authors.initials: C
authors.lastname: Matte-Martone
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.forename: Srividhya
authors.initials: S
authors.lastname: Venkatesan
authors.forename: Hung Sheng
authors.initials: HS
authors.lastname: Tan
authors.forename: Jennifer
authors.initials: J
authors.lastname: McNiff
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Derry
authors.initials: D
authors.lastname: Roopenian
authors.forename: Susan
authors.initials: S
authors.lastname: Kaech
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology / Q000502:physiology; D007156:Immunologic Memory / Q000502:physiology; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D008216:Lymphocytic Choriomeningitis / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D014019:Tissue Donors; D014181:Transplantation Immunology; D015854:Up-Regulation; D014611:Vaccination
chemical_list: D015778:Minor Histocompatibility Antigens; C114735:minor H antigen H60