CD28/B7 interactions are required for sustaining the graft-versus-leukemia effect of delayed post-bone marrow transplantation splenocyte infusion in murine recipients of myeloid or lymphoid leukemia cells.
Graft-vs-leukemia (GVL) can reduce relapse rates after bone marrow transplantation (BMT). Delayed lymphocyte infusion (DLI) post-BMT can mediate a potent GVL effect with less graft-vs-host disease (GVHD) than would be observed if given early post-BMT. In vivo CD28/B7 blockade can reduce GVHD lethality, and B7 ligand expression can augment an antitumor immune response in mice. To examine the role of CD28/B7 interactions in DLI-mediated GVL, we established murine allogeneic BMT models in C57BL/6 (B6) recipients of C1498 (B6 acute myeloid leukemia) or EL4 (B6 acute T cell leukemia) that closely mimic human GVL. Recipients of C1498 and DLI had a marked reduction in relapse. GVL was blocked by anti-B7 mAb infusion. In contrast, recipients of EL4 cells and B10.BR DLI had a more modest GVL effect. The forced expression of B7-1 on EL4 cells markedly augmented the GVL effect of DLI, in contrast to the forced expression of B7-2 on EL4 cells. Relapse rates observed in recipients of C1498-B7-1 and DLI were significantly lower than in recipients of parental C1498 cells. We conclude that the administration of anti-B7 mAbs may impair the GVL effect of DLI and that the forced expression of B7-1 ligands stimulates a GVL effect without adversely affecting the GVHD lethality effect of DLI.
Blazar
B R
BR
Department of Pediatrics, University of Minnesota Hospital and Clinic, Minneapolis 55455, USA.
Taylor
P A
PA
Boyer
M W
MW
Panoskaltsis-Mortari
A
A
Allison
J P
JP
Vallera
D A
DA
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D051940:B7-2 Antigen; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation; D006087:Graft vs Host Reaction / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins