Immunosuppressive effects of (131)I-anti-CD45 antibody in unsensitized and donor antigen-presensitized H2-matched, minor antigen-mismatched murine transplant models.
Iodine-131-labeled anti-CD45 antibody has been added to conventional hematopoietic stem cell transplant preparative regimens to deliver targeted radiation to hematopoietic tissues, with the goal of decreasing relapse rates without increasing toxicity. However, higher radiation doses could be delivered to leukemia cells by antibody if the systemic therapy were decreased or eliminated. To examine the ability of (131)I-anti-CD45 antibody to provide sufficient immunosuppression for transplantation across allogeneic barriers, T-cell-depleted BALB.B marrow was transplanted into H2-compatible B6-Ly5(a) mice after (131)I-30F11 (rat antimurine CD45) antibody with or without varying dose levels of total body irradiation (TBI). Groups of five or six recipient mice per (131)I or TBI dose level per experiment were given tail vein injections of 100 microg of (131)I-labeled 30F11 antibody 4 days before marrow infusion, with or without TBI on day 0. Engraftment, defined as > or =50% donor B cells at 3 months posttransplant, 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 allotypes and for CD3. Donor engraftment of > or =80% recipient mice was achieved with either 8 Gy of TBI or 0.75 mCi of (131)I-30F11 antibody, which delivers an estimated 26 Gy to bone marrow. Subsequent experiments determined the dose of TBI alone or TBI plus 0.75 mCi of (131)I-30F11 antibody necessary for engraftment in recipient mice that had been presensitized to donor antigens before transplant, a setting requiring more stringent immunosuppression. Engraftment was seen in > or =80% of presensitized recipients surviving after 14-16 Gy of TBI or 12-14 Gy of TBI and 0.75 mCi of (131)I-30F11 antibody. However, only 28 of 69 (41%) presensitized mice receiving 10-16 Gy of TBI alone survived, presumably because of rejection of donor marrow and ablation of host hematopoiesis. In contrast, 29 of 35 (83%) presensitized mice receiving (131)I-30F11 antibody and 10-14 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 (131)I-30F11 antibody permitted engraftment of donor marrow. These results suggest that targeted radiation delivered by (131)I-anti-CD45 antibody provides sufficient immunosuppression to replace an appreciable portion of the TBI dose used in matched sibling hematopoietic stem cell transplant.
Ruffner
K L
KL
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Martin
P J
PJ
Hussell
S
S
Nourigat
C
C
Fisher
D R
DR
Bernstein
I D
ID
Matthews
D C
DC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007114:Immunization; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000379:methods; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D017493:Leukocyte Common Antigens