Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease
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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.
KeywordsChronic granulomatous disease Haploidentical hematopoietic cell transplantation Non-myeloablative conditioning Anti-CD40 ligand therapy Tolerance
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.
- 6.Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J Exp Med. 1997;185(2):207–18.PubMedCentralPubMedCrossRefGoogle Scholar
- 19.Tomita Y, Sachs DH, Khan A, Sykes M. Additional monoclonal antibody (mAB) injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mABs and 3-Gy whole body irradiation. Transplantation. 1996;61(3):469–77.PubMedCrossRefGoogle Scholar
- 27.Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985–2000. Blood. 2002;100(13):4344–50.PubMedCrossRefGoogle Scholar
- 33.Fehr T, Takeuchi Y, Kurtz J, Wekerle T, Sykes M. Early regulation of CD8 T cell alloreactivity by CD4+ CD25- T cells in recipients of anti-CD154 antibody and allogeneic BMT is followed by rapid peripheral deletion of donor-reactive CD8+ T cells, precluding a role for sustained regulation. Eur J Immunol. 2005;35(9):2679–90.PubMedCrossRefGoogle Scholar
- 34.Kurtz J, Shaffer J, Lie A, Anosova N, Benichou G, Sykes M. Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells. Blood. 2004;103(11):4336–43.PubMedCrossRefGoogle Scholar