Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice.
We have previously shown that the keys to high-level nontoxic chimerism in syngeneic models are stem cell toxic, nonmyelotoxic host treatment as provided by 100-cGy whole-body irradiation and relatively high levels of marrow stem cells. This approach was unsuccessful in H-2 mismatched B6.SJL to BALB/c marrow transplants, but with tolerization, stable multilineage chimerism was obtained. Ten million B6.SJL spleen cells were infused intravenously into BALB/c hosts on day -10 and (MR-1) anti-CD40 ligand monoclonal antibody (mAb) injected intraperitoneally at varying levels on days -10, -7, -3, 0, and +3 and the BALB/c mice irradiated (100 cGy) and infused with 40 million B6.SJL/H-2 mismatched marrow cells on day 0. Stable multilineage chimerism at levels between 30% to 40% was achieved in the great majority of mice at 1.6 mg anti-CD40 ligand mAb per injection out to 64 weeks after transplantation, without graft-versus-host disease. The transplanted mice were also tolerant of donor B6.SJL, but not third-party CBA/J skin grafts at 8 to 9 and 39 to 43 weeks after marrow transplantation. These data provide a unique model for obtaining stable partial chimerism in H-2 mismatched mice, which can be applied to various clinical diseases of man such as sickle cell anemia, thalassemia, and autoimmune disorders.
Quesenberry
P J
PJ
Cancer Center, University of Massachusetts Medical Center, Worcester, MA 01655, USA. peter.quesenberry@umassmed.edu
Zhong
S
S
Wang
H
H
Stewart
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001787:Blood Group Incompatibility / Q000188:drug therapy / Q000517:prevention & control*; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods* / Q000592:standards; D023201:CD40 Ligand / Q000276:immunology; D017690:Cell Transplantation; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control; D006183:H-2 Antigens / Q000276:immunology*; D007108:Immune Tolerance; D007114:Immunization; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D023421:Models, Animal; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000276:immunology / Q000379:methods / Q000592:standards; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D023201:CD40 Ligand