Immunosuppressive effects of I-131-anti-CD45 antibody in unsensitized and donor antigen-presensitized H2-matched, minor antigen-mismatched murine transplant models

Iodine-131-laheled anti-CD45 antibody has been added to conventional hemato poietic stem cell transplant preparative regimens to deliver targeted radia tion to hematopoietic tissues, with the goal of decreasing relapse rates wi thout increasing toxicity. However higher radiation doses could be delivere d to leukemia cells by antibody if the systemic therapy mere decreased or e liminated, To examine the ability of T-131-anti-CD45 antibody to provide su fficient immunosuppression for transplantation across allogeneic barriers, T-cell-depleted BALB.B marrow was transplanted into H2-compatible B6-Ly(5a) mice after I-131-30F11 (rat antimurine CD45) antibody with or without vary ing dose levels of total body irradiation (TBI), Groups of five or six reci pient mice per I-131 Or TBI dose level per experiment were given tail vein injections of 100 mug of I-131-labeled 30F11 antibody 4 days before marrow infusion, with or without TBI on day 0, Engraftment, defined as greater tha n or equal to 50% donor B cells at 3 months post-transptant, was determined by two-color flow cytometric analysis of peripheral blood granulocytes, T cells, and B cells using antibodies specific for donor and host (CD45 allot ypes and for CD3, Donor engraftment of greater than or equal to 80% recipie nt mice was achieved with either 8 Gy of TBI or 0.75 mCi of I-131-30F11 ant ibody, which delivers an estimated 26 Gy to bone marrow. Subsequent experim ents determined the dose of TBI alone or TBI plus 0.75 mCi of I-131-30F11 a ntibody necessary for engraftment in recipient mice that had been presensit ized to donor antigens before transplant, a setting requirings more stringe nt immunosuppression, Engraftment was seen in greater than or equal to 80% of presensitized recipients surviving after 14-16 Gy of TBI of 12-14 Gy of TBI and 0.75 mCi of I-131-30F11 antibody. However, only 28 of 69 (41%) pres ensitized mice receiving 10-16 Gy of TBI alone survived, presumably because of rejection of donor marrow and ablation of host hematopoiesis, In contra st, 29 of 35 (53%) presensitized mice receiving I-131-30F11 antibody and 12 -14 Gy of TBI survived, presumably because the additional immunosuppression provided by estimated radiation doses of 53 Gy to lymph nodes and 81 Gy to spleen from 0.75 mCi of I-131-30F11 antibody permitted engraftment of dono r marrow. These results suggest that targeted radiation delivered by I-131- anti-CD45 antibody provides sufficient immunosuppression to replace an appr eciable portion of the TBI dose used in matched sibling hematopoietic stem cell transplant.