Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficient activity of the iduronate-2-sulfatase. This leads to accumulation of glycosaminoglycans (GAGs) in the lysosomes of various cells. Although it has been proposed that bone marrow transplantation (BMT) may have a beneficial effect for patients with MPS II, the requirement for donor-cell chimerism to reduce GAG levels is unknown. To address this issue, we transplanted various ratios of normal and MPS II bone marrow cells in a mouse model of MPS II and analyzed GAG accumulation in various tissues. Chimerism of whole leukocytes and each lineage of BMT recipients’ peripheral blood was similar to infusion ratios. GAGs were significantly reduced in the liver, spleen, and heart of recipients. The level of GAG reduction in these tissues depends on the percentage of normal-cell chimerism. In contrast to these tissues, a reduction in GAGs was not observed in the kidney and brain, even if 100 % donor chimerism was achieved. These observations suggest that a high degree of chimerism is necessary to achieve the maximum effect of BMT, and donor lymphocyte infusion or enzyme replacement therapy might be considered options in cases of low-level chimerism in MPS II patients.
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Acknowledgments
The authors thank Joseph Muenzer of the University of North Carolina at Chapel Hill for providing the MPS II mice. We also thank Taku Sato of Tokyo Medical and Dental University for helping with the flow cytometry study. Finally, we thank the members of the Laboratory Animal Facility at The Jikei University School of Medicine for help with the animal studies. This work was supported by a KAKENHI Grant (No. 25860884) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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The data in the manuscript are original and the manuscript is not under consideration for publication elsewhere. None of the manuscript contents have been previously published except in abstract form.
Conflict of interest
Toya Ohashi has active research support from Genzyme Japan Co., Ltd. and Shire Japan.
Hiroyuki Ida has active research support from Genzyme Japan Co., Ltd. and Shire Japan Co., Ltd.
Kentaro Yokoi, Kazumasa Akiyama, Eiko Kaneshiro, Takashi Higuchi, Yohta Shimada, Hiroshi Kobayashi, Masaharu Akiyama, Makoto Otsu, and Hiromitsu Nakauchi declare that they have no conflict of interest.
This support has been fully disclosed and is managed under a Memorandum of Understanding with the Conflict of Interest Resolution Board of The Jikei University School of Medicine.
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K.Y., K.A. and T.O. designed and conducted research; E.K., H.H., Y.S. and H.K. performed experiments and analysed data; K.Y. wrote the paper; M.A., M.O., H.N., T.O., and H.I. discussed data and edited the paper.
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All intuitional and national guidelines for the care and use of laboratory animals were followed.
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Communicated by: Marc Patterson
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Yokoi, K., Akiyama, K., Kaneshiro, E. et al. Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II. J Inherit Metab Dis 38, 333–340 (2015). https://doi.org/10.1007/s10545-014-9800-x
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DOI: https://doi.org/10.1007/s10545-014-9800-x