title: In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease.
abstract: Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8(+) cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigen-presenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4(+) or CD8(+) T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-γ and TNF-α or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8(+) T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.
authors.affiliation: University Children's Hospital, Ulm, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hartmann
authors.forename: F
authors.initials: F
authors.lastname: Leithäuser
authors.forename: C
authors.initials: C
authors.lastname: Albers
authors.forename: J
authors.initials: J
authors.lastname: Duyster
authors.forename: P
authors.initials: P
authors.lastname: Möller
authors.forename: K-M
authors.initials: KM
authors.lastname: Debatin
authors.forename: G
authors.initials: G
authors.lastname: Strauss
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D016207:Cytokines / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016207:Cytokines; D007519:Isoantigens