Allospecific CD4+, Th1/Th2 and CD8+, Tc1/Tc2 populations in murine GVL: type I cells generate GVL and type II cells abrogate GVL.
Donor CD4+ and CD8+ T cells mediate graft-vs.-leukemia (GVL) responses in the allogeneic bone marrow transplantation (alloBMT) setting. To evaluate the role of functional T cell subsets in the mediation of GVL, alloreactive donor CD4+ (Th1/Th2) and CD8+ (Tc1/Tc2) T cells of defined cytokine phenotype were generated by in vitro culture. A leukemia/transplantation model (B6 into B6C3F1; 1050 cGy host irradiation) was established using the bcr/abl-transfected myeloid leukemia line, 32Dp210 (P210; H-2k). Leukemia control mice (1X10(4) P210 cells per recipient) died at day 12.0 post-BMT. Recipients of the CD4+, Th1-type or CD8+, Tc1-type populations were conferred a survival advantage (death at 20.7 and 23.5 days post-BMT, respectively). In contrast, the CD4+, Th2-type population did not mediate GVL (death at 12.3 days). Furthermore, cell mixing experiments demonstrated that the Th2 subset abrogated both Th1- and Tc1-mediated GVL. The CD8+, Tc2 population, which secreted type II cytokines and lysed the P210 leukemia target in vitro, mediated GVL in some experiments; interestingly, the magnitude of Tc2-mediated GVL was inversely related to the level of interleukin-10 (IL-10) secreted in vitro by the Tc2 population. These studies therefore indicate that alloreactive T cells of type I phenotype maximally generate GVL, and that type I/type II interactions are an important consideration for allogeneic transplantation in the setting of leukemic hosts.
Fowler
D H
DH
Transplantation Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA. dhfowler@helix.nih.gov
Breglio
J
J
Nagel
G
G
Hirose
C
C
Gress
R E
RE
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D016207:Cytokines; D007519:Isoantigens; D016753:Interleukin-10