Transfer of idiotypic protein primed allogeneic marrow grafts elicits potent graft-versus-myeloma effects in mice.
The active immunization of bone marrow (BM) donors with myeloma immunoglobulin (Ig) results in an idiotypic T cell response that can be transferred to the recipient. Using a murine model we evaluated the effectiveness, side-effects and underlying mechanisms of this approach. Balb/c (H-2d) mice were given a dose of HOPC-1F myeloma cells secreting the monoclonal IgG2a followed by lethal total body irradiation (7.5 Gy) 2 days later and a subsequent transplantation of 2 x 10(7) allogeneic MHC-matched DBA/2-derived marrow cells. Donors were pre-immunized with three i.p. injections of HOPC(IgG2a) or control Ig given with incomplete Freund's adjuvants (IFA) spaced 1 week apart. In some experiments, donor-spleen cells were additionally transferred 2 h post transplant. Injection of HOPC-myeloma led to death of all animals after a median survival time (MST) of 42 days. A lethal dose of TBI followed by transfer of unmanipulated marrow grafts plus splenocytes resulted in moderate antimyeloma effects with 8% of mice achieving long-term survival. Nearly the same results were obtained after transplantation of BM immunized with the control Ig. In contrast, transplantation of marrow grafts from HOPC(IgG2a) immunized donors exerted a significant GVM effect with 63% long-term survival for more than 180 days. The additional transfer of 2 x 10(7) immune splenocytes derived from the same donor resulted in even stronger anti-myeloma effects (FFR 87%). No increase in the incidence of severe acute GVHD was observed. In vitro data suggest that allogeneic CD8+ idiotype-specific T cells may be the major effector cells. Our results demonstrate that active immunization of the donor with the myeloma-specific Ig can induce powerful graft-versus-myeloma effects after allogeneic BMT.
Department of Internal Medicine II, University of Kiel, Germany.
M
M
Zeis
J
J
Steinmann
E
E
Petrela
G
G
Hartung
N
N
Schmitz
L
L
Uharek
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007130:Immunoglobulin Idiotypes / Q000276:immunology* / Q000627:therapeutic use*; D007136:Immunoglobulins / Q000627:therapeutic use; D007267:Injections; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009194:Myeloma Proteins / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D014184:Transplantation, Homologous / Q000379:methods; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014611:Vaccination
D007130:Immunoglobulin Idiotypes; D007136:Immunoglobulins; D009194:Myeloma Proteins; C017551:myeloma immunoglobulins