Mechanisms of the antitumor responses and host-versus-graft reactions induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: a critical role for recipient CD4+ T cells and recipient leukocyte infusion-derived IFN-gamma-producing CD8+ T cells.
Surprisingly, antitumor responses can occur in patients who reject donor grafts following nonmyeloablative hemopoietic cell transplantation. In murine mixed chimeras prepared with nonmyeloablative conditioning, we previously showed that recipient leukocyte infusions (RLI) induced loss of donor chimerism, IFN-gamma production, and antitumor responses against host-type tumors. However, the mechanisms behind this phenomenon remain to be determined. We now demonstrate that the effects of RLI are mediated by distinct and complex mechanisms. Donor marrow rejection is induced by RLI-derived alloactivated T cells, which activate non-RLI-derived, recipient IFN-gamma-producing cells. RLI-derived CD8 T cells induce the production of IFN-gamma by both RLI and non-RLI-derived recipient cells. The antitumor responses of RLI involve mainly RLI-derived IFN-gamma-producing CD8 T cells and recipient-derived CD4 T cells and do not involve donor T cells. The pathways of donor marrow and tumor rejection lead to the development of tumor-specific cell-mediated cytotoxic responses that are not due to bystander killing by alloreactive T cells.
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital, Harvard Medical School, 13th Street, Boston, MA 02129, USA.
Marie-Therese
MT
Rubio
Toshiki I
TI
Saito
Kristin
K
Kattleman
Guiling
G
Zhao
Jennifer
J
Buchli
Megan
M
Sykes
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006789:Host vs Graft Reaction / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D017708:Leukocyte Transfusion / Q000379:methods; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods
D007371:Interferon-gamma