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.
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We thank Dr. A. S. Knisely for critical reading of the manuscript, Dr. Michiko Abe for the Aspergillus fumigatus debris suspension, Dr. Yasuteru Urano for fluorescent probes and his technical advice, Dr. Yasunori Ota for histopathological analysis, and Dr. Masanori Nojima for statistical analysis. This work was supported in part of by a JSPS KAKENHI Grant-in-Aid for Yasuo Takeuchi and Makoto Otsu, and by grants from the Ministry of Health, Labor and Welfare and National Center for Child Health and Development (M. Onodera).
Conflict of interest
The authors declare that they have no conflict of interest.
This work was performed in the Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo.
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Takeuchi, Y., Takeuchi, E., Ishida, T. et al. Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease. Int J Hematol 102, 111–120 (2015) doi:10.1007/s12185-015-1799-8
- Chronic granulomatous disease
- Haploidentical hematopoietic cell transplantation
- Non-myeloablative conditioning
- Anti-CD40 ligand therapy