Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (<20 % donor cells), indicating induction of donor-specific tolerance. The regimen induced mild myelosuppression without severe acute complications. Stable chimerism was therapeutic, as it suppressed cutaneous granuloma formation in an in vivo test suited for evaluation of treatment efficacy in murine CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity.
Division of Nephrology, Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan.
Yasuo
Y
Takeuchi
Emiko
E
Takeuchi
Takashi
T
Ishida
Masafumi
M
Onodera
Hiromitsu
H
Nakauchi
Makoto
M
Otsu
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D006085:Graft Survival; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006239:Haplotypes; D006410:Hematopoiesis; D007249:Inflammation; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation
D019013:CD40 Antigens; D006183:H-2 Antigens; D017382:Reactive Oxygen Species; D023201:CD40 Ligand