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-2(d)) mice were given a dose of HOPC-1F myeloma cells secreting the monoclonal IgG,, 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 HOPCIgG2a Or control Ig given with incomplete Freund's adjuvants (LFA) 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 HOPCIgG2a immunized donors exerted a significant GVM effect with 63% long-term survival for more than 180 days. The additional transfer of 2 x 107 immune splenocytes derived from the saline 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,