Adoptive immunotherapy of BCR-ABL-induced chronic myeloid leukemia-like myeloproliferative disease in a murine model.
Donor leukocyte infusion (DLI) can induce graft-versus-leukemia (GvL) reactions in patients with chronic myeloid leukemia (CML) relapsing after allogeneic bone marrow transplantation (BMT), but the mechanisms of the antileukemic effect of DLI are unknown, and the procedure is complicated by graft-versus-host disease (GvHD) and graft failure. Here, we adapted a murine retroviral BMT model of Philadelphia(+) leukemia by combining allogeneic bone marrow (BM) from C57Bl/6 (H-2(b)) mice with BCR-ABL-transduced Balb/c (H-2(d)) BM, inducing mixed chimerism and myeloproliferative disease in recipients resembling relapse of CML following allogeneic BMT. Infusions of allogeneic splenocytes eliminated BCR-ABL-induced CML-like disease in the majority of mixed chimeras, with significant GvL effects mediated by both CD4(+) and CD4(-) cells. BCR-ABL-induced acute B-lymphoblastic leukemia was also eradicated by DLI in major histocompatibility complex (MHC)-mismatched chimeras. Most DLI-treated mice converted to full allogeneic chimerism but succumbed frequently to GvHD or graft failure. When MHC-matched B10.D2 (H-2(d)) mice were the allogeneic donors, CML-like disease was more resistant to DLI. These results suggest that depletion of CD8(+) cells from DLI could impair GvL against CML, while increased MHC disparity between donor and recipient may improve the responsiveness of Philadelphia(+) B-lymphoblastic leukemia to DLI.
Krause
Daniela S
DS
Center for Blood Research, Institute for Biomedical Research, Harvard Medical School, Boston, MA, USA.
Van Etten
Richard A
RA
D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl; D006650:Histocompatibility Testing; D016219:Immunotherapy, Adoptive; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009196:Myeloproliferative Disorders / Q000276:immunology / Q000628:therapy*; D018183:Transplantation Chimera
D016044:Fusion Proteins, bcr-abl