Influence of dimethyl myleran on tolerance induction and immune function in major histocompatibility complex-haploidentical murine bone-marrow transplantation.
To study murine major histocompatibility complex (MHC)-haploidentical bone-marrow transplantation (BMT), B6C3F1 mice (H-2b/k) underwent BMT using syngeneic [B6C3F1 (H-2b/k)], haploidentical [CB6F1 (H-2d/b)], or fully allogeneic [DBA/2 (H-2d)] donor mice. As pretreatment, dimethyl myleran (DMM), an alkylating agent that produces effective myeloablation but little immunosuppression, was used with total body irradiation (TBI). Four conditioning regimens were studied: TBI 800 rads (1 rad = 0.01 Gy), TBI 950 rads, TBI 800 rads plus DMM (0.2 mg per mouse), and TBI 950 rads plus DMM. Survival rates, chimerism, proliferative responses in mixed-lymphocyte culture, specific cell-mediated lympholysis, and in vivo plaque-forming cell responses to several antigens were compared. TBI 800 rads plus DMM was maximally effective. Haploidentical BMT was as successful in inducing long-term survival and immune and hematologic reconstitution as was syngeneic BMT. This regimen plus haploidentical BMT of T-cell-purged marrow yielded survivors tolerant of donor and recipient major histocompatibility complex. Such myeloablation and immunosuppression prevented graft rejection, immunodeficiency due to histoincompatibility, and damage to a radiosensitive cell population. A microenvironmental influence crucial to some antibody responses was thus revealed. Delayed recovery of antibody production after BMT in humans may be due partly to suboptimal myeloablation or excess irradiation.
Ishii
E
E
Department of Pediatrics, All Children's Hospital, University of South Florida, St. Petersburg 33701.
Gengozian
N
N
Good
R A
RA
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D007111:Immunity, Cellular; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D011828:Radiation Chimera
C002037:dimethylmyleran; D002066:Busulfan