Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy.
Hematopoietic macrochimerism, established by bone marrow transplantation, can be used as an approach for treating autoimmune disease and inducing transplant tolerance. In this study, we investigated whether a stable, high level of fully MHC-mismatched hematopoietic macrochimerism can be induced by using irradiation-free protocols, and whether rapamycin and T cell costimulatory blockades (anti-CD40L monoclonal antibody (mAb) and CTLA4Ig) as post-transplant treatment promote bone marrow engraftment. Donor-specific blood transfusion (DST), anti-lymphocyte serum (ALS), busulfan, and cyclophosphamide were given pretransplantation. Balb/c (H-2(d)) bone marrow cells, at a dose of 4 x 10(7), were infused into each C57BL/6 mouse (H-2(b)). Rapamycin, anti-CD40L mAb, and CTLA4Ig were then administered, either alone or in combination. Without ALS or busulfan and cyclophosphamide, macrochimerism can only rarely be induced. Donor-specific transfusion (DST) enhances induction of hematopoietic macrochimerism. Rapamycin, anti-CD40L mAb and CTLA4Ig, alone or in combination, induce a stable and high level of hematopoietic macrochimerism. In the chimeric mice, donor-derived cells were detected in all lymphohematopoietic tissues and donor-specific tolerance was induced in vitro. We conclude that a stable and high level of fully MHC-mismatched hematopoietic macrochimerism can be induced in mice after transplanting a single modest dose of bone marrow cells without irradiation. Rapamycin and T cell costimulatory blockade as post-transplant treatment promote bone marrow engraftment.
Wu
T
T
Diabetes Institute for Immunology and Transplantation, and Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Sozen
H
H
Luo
B
B
Heuss
N
N
Kalscheuer
H
H
Lan
P
P
Sutherland
D E R
DE
Hering
B J
BJ
Guo
Z
Z
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006648:Histocompatibility; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000008:administration & dosage*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D020123:Sirolimus