In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease
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In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease. / Hartmann, N; Leithäuser, F; Albers, C; Duyster, Justus; Möller, P; Debatin, K-M; Strauss, Gudrun.
In: LEUKEMIA, Vol. 25, No. 5, 05.2011, p. 848-55.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease
AU - Hartmann, N
AU - Leithäuser, F
AU - Albers, C
AU - Duyster, Justus
AU - Möller, P
AU - Debatin, K-M
AU - Strauss, Gudrun
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
KW - Animals
KW - Blotting, Western
KW - CD8-Positive T-Lymphocytes
KW - Cytokines
KW - Female
KW - Flow Cytometry
KW - Graft vs Host Disease
KW - Graft vs Tumor Effect
KW - Isoantigens
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Inbred DBA
KW - Spleen
KW - Survival Rate
KW - T-Lymphocytes, Cytotoxic
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/leu.2011.16
DO - 10.1038/leu.2011.16
M3 - SCORING: Journal article
C2 - 21331071
VL - 25
SP - 848
EP - 855
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 5
ER -