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Post-transplantation cyclophosphamide restores early B-cell lymphogenesis that suppresses subsequent chronic graft-versus-host disease

Bone Marrow Transplantation volume 56, pages 956–959 (2021)Cite this article

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In recent years, many studies have focused on the abnormality of B-cell immunity as a major factor in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2]. Sarantopoulos et al. firstly reported abnormal B-cell homeostasis in the post-transplant environment where naïve B-cell lymphopenia and excessive B-cell activation factor (BAFF) promoted the responsiveness of B cells to antigens, and increased survival of activated B cells [3, 4]. Ensuing studies demonstrated that follicular helper T cells (Tfhs) promoted the differentiation from naïve B cells into germinal center B cells, which may result in the aberrant production of IgG alloantibodies causing tissue damage in cGVHD-target organs [5, 6]. Based on these findings, therapies targeting activated B cells have been developed for patients with cGVHD [7,8,9,10]. However, the factors that may be associated with naïve B lymphopenia early after transplant, which could trigger to form the basal pathogenesis of chronic GVHD, have not been well studied.

In this study, we examined early immune reconstitution, especially early B-cell lymphogenesis and differentiation, in three different types of alternative-donor transplants in comparison with HLA-matched peripheral blood transplants. Laboratory studies were undertaken in 35 adult patients who received HLA-mismatched allogeneic grafts including related haploidentical peripheral blood with post-transplant cyclophosphamide (PTCy) (PTCy-haplo), unrelated cord blood transplant (CBT), T-cell-replete haploidentical peripheral blood with low-dose anti-thymocyte globulin (ATG-haplo), and HLA-matched related or unrelated peripheral blood (Supplementary Table 1). We first performed an exploratory examination on the early reconstitution of various lymphocyte subsets (Supplementary Fig. 1). At 4 weeks, recovery of T-cell subsets was significantly delayed in HLA-mismatched compared to HLA-matched transplants. However, the proportion of regulatory T cells (Tregs) was relatively high in PTCy-haplo compared to HLA-matched transplants, suggesting that PTCy could deplete alloreactive effector T cells while enhancing the recovery of donor-derived Tregs that were reported as resistant to PTCy by an aldehyde dehydrogenase-based mechanism [11]. The number of B cells was very small at 4 weeks in all transplant types, including HLA-matched transplants, but thereafter gradually increased over the 8 weeks. Particularly, B-cell recovery after 4 weeks was prominent in PTCy-haplo as compared to other types of transplant.

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Fig. 1: Early B-cell lymphogenesis and differentiation after allogeneic HSCT.

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Acknowledgements

The authors thank Kyoko Maeda and Hiromi Nakashima for organizing the clinical samples. We also appreciate all staff at the Central Research Laboratory, Okayama University Medical School. This work was supported by research funding from the Japan Society for the Promotion of Science KAKENHI (Grant No. 20K08753).

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  1. Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Miki Iwamoto, Shuntaro Ikegawa, Takumi Kondo, Yusuke Meguri, Makoto Nakamura, Yasuhisa Sando, Hiroyuki Sugiura, Yuichi Sumii, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda & Ken-ichi Matsuoka

  2. Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan

    Miki Iwamoto & Misako Shibakura

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Correspondence to Ken-ichi Matsuoka.

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Iwamoto, M., Ikegawa, S., Kondo, T. et al. Post-transplantation cyclophosphamide restores early B-cell lymphogenesis that suppresses subsequent chronic graft-versus-host disease. Bone Marrow Transplant 56, 956–959 (2021). https://doi.org/10.1038/s41409-020-01100-0

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