Novel Duchenne muscular dystrophy treatment through myoblast transplantation tolerance with anti-CD45RB, anti-CD154 and mixed chimerism.
Duchenne muscular dystrophy (DMD) is a fatal disease caused by a defect in the skeletal muscle protein, dystrophin. One potential therapy for DMD involves transplantation of myoblasts from normal individuals. Unfortunately, myoblast allografts are particularly immunogenic and transplant tolerance in dystrophic (mdx/mdx) mice has not yet been achieved despite using strategies successful in other allograft models. Here, we attempted to induce 'central tolerance' using either haplo- or fully allogeneic bone marrow after conditioning with low-dose (3 Gy) whole body irradiation and anti-CD154 or anti-CD45RB mAbs. With one exception, these mice lacked persistent chimerism, long-term survival of myoblast allografts, or tolerance. In contrast, the addition of anti-CD45RB to anti-CD154 uniformly resulted in long-lived high-level mixed chimerism, long-term (>100 days) engraftment of allogeneic myoblasts and deletion of donor-reactive cells. Moreover, all recipients exhibited tolerance to second myoblast allografts or donor-specific tolerance to skin transplants performed >80 days after the initial graft. Thus, we now report that anti-CD45RB synergizes with anti-CD40L to promote stable mixed chimerism and robust tolerance to myoblast allografts for the first time. This novel protocol may be applicable to future clinical trials in myoblast transplantation for treatment of DMD and for transplantation of other immunogenic allografts.
Unité de Recherche en Génétique Humaine, Centre de Recherche du CHUL, Université Laval, Québec, Canada.
Geoffrey
G
Camirand
Joël
J
Rousseau
Marie-Eve
ME
Ducharme
David M
DM
Rothstein
Jacques P
JP
Tremblay
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000737:chemistry / Q000276:immunology*; D017690:Cell Transplantation; D002678:Chimera; D016189:Dystrophin / Q000737:chemistry / Q000502:physiology; D005434:Flow Cytometry; D006086:Graft vs Host Disease; D007108:Immune Tolerance; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology; D009132:Muscles / Q000166:cytology* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance
D000911:Antibodies, Monoclonal; D016189:Dystrophin; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens