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

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

doi:10.1038/s41409-020-01100-0

Cited by 9 publications

(8 citation statements)

References 13 publications

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“…Using a murine haploHSCT with PTCy model, Matsuoka et al evaluated the reconstitution of B cells, Tfh cells and Tregs. 82 Tfh cells were present at a low frequency in PTCy -treated recipients, whereas Tregs and B cells were present at higher frequencies than in the non-PTCy controls. This suggests that PTCy can induce the expansion of Tregs and increase naïve B cell recovery without causing the early emergence of Tfh cells in lymph nodes, resulting in diverse T and B cell reconstitution.…”

Section: B-cell Reconstitutionmentioning

confidence: 81%

Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

Maeda

2021

J Clin Exp Hematopathol

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As HLA haploidentical related donors are quickly available, HLA haploidentical hematopoietic stem cell transplantation (haploHSCT) using high-dose post-transplant cyclophosphamide (PTCy) is now widely used. Recent basic and clinical studies revealed the details of immune reconstitution after T-cell replete haploHSCT using PTCy. T cells and NK cells in the graft proliferate abundantly at day 3 post-haploHSCT, and the PTCy eliminates these proliferating cells. After ablation of proliferating mature cells, donor-derived NK cell reconstitution occurs after the second week; however, recovering NK cells remain functionally impaired for at least several months after haploHSCT. PTCy depletes proliferating cells, resulting in the preferential accumulation of Treg and CD4+ T cells, especially the memory stem T cell (T SCM ) phenotype. T SCM capable of both self-renewal and differentiation into effector T cells may play an important role in the first month of immune reconstitution. Subsequently, de novo T cells progressively recover but their levels remain well below those of donor CD4+ T cells at the first year after haploHSCT. The phenotype of recovering T cells after HSCT is predominantly effector memory, whereas B cells are predominantly phenotypically naive throughout the first year after haploHSCT. B cell recovery depends on de novo generation and they are not detected until week 4 after haploHSCT. At week 5, recovering B cells mostly exhibit an unconventional transitional cell phenotype and the cell subset undergoes maturation. Recent advances in immune reconstitution have improved our understanding of the relationship between haploHSCT with PTCy and the clinical outcome.

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Section: B-cell Reconstitutionmentioning

confidence: 81%

Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

Maeda

2021

J Clin Exp Hematopathol

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“…Furthermore, BTK plays an essential role in the BCR and the pre-BCR signaling pathway, which regulates B cell development, proliferation, survival, and function (58,59). Because ITK selective inhibition does not directly act on BTK in donor B cells during the early stage following HSCT, this strategy may provide a novel strategy for immune regulation that can selectively modulate acute GVHD-responsible T cells without impairing the early posttransplant BTK activation that is required to restore B cell-mediated immunity and reduce the risk of infectious events and subsequent chronic GVHD (12,60).…”

Section: Discussionmentioning

confidence: 99%

“…Although acute and chronic GVHD differ in their clinical characteristics and pathogenesis, recent studies have indicated that acute GVHD can trigger the pathogenesis of chronic GVHD (6,(10)(11)(12), suggesting that prevention of acute GVHD is critical for maintaining a high quality of life for long-term survivors (13,14).…”

Section: Introductionmentioning

confidence: 99%

Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells

et al. 2021

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Graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). IL-2-inducible T cell kinase (ITK), a TEC cytoplasmic tyrosine kinase, has an essential role in T cell development and receptor signaling. The ITK/Bruton tyrosine kinase inhibitor ibrutinib has been shown to improve chronic GVHD symptoms; however, the effect of ITK selective inhibition on acute GVHD remains unclear. In this study, we evaluated the pharmacological effects of an ITK selective inhibitor (ITKsi) on acute GVHD using murine bone marrow transplantation models. First, we found that CD4 + T cell differentiation toward Th1, Th2, or Th17 was inhibited following ITKsi treatment in a dose-dependent manner while maintaining regulatory T cells in the presence of alloantigens both in vitro and in vivo. ITKsi preferentially inhibited inflammatory cytokine production and in vivo proliferation of alloreactive T cells. We then demonstrated that short-term exposure of donor graft cells to ITKsi significantly delayed the onset of GVHD-associated mortality without compromising the donor cell engraftment and the graft-versus-tumor effect, indicating the potential of ITK selective inhibition in the setting of clinical allogeneic HSCT. These findings suggest that ITK is a potential therapeutic target against GVHD, and the pharmacological ITK inhibitor may serve as a novel strategy for immune regulation after HSCT. ImmunoHorizons, 2021, 5: 424-437.

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“…The indispensable role of donor-derived Tregs in preventing GVHD in PTCy was shown in a mouse model (98), which suggests that PTCy-based GVHD prophylaxis may preferentially promote the reconstitution of Tregs in a clinical setting. However, there are limited data on Treg reconstitution after HSCT with PTCy-based GVHD prophylaxis using human clinical samples (99)(100)(101)(102). Our and other groups recently reported the reconstitution of lymphocyte subsets between HLA-haploidentical PTCy-based HSCT (PTCy-haplo) as compared to HLA-identical donor HSCT using conventional GVHD prophylaxis (101,102).…”

Section: The Effect Of Ptcy On Treg Homeostasis After Hsctmentioning

confidence: 99%

“…However, there are limited data on Treg reconstitution after HSCT with PTCy-based GVHD prophylaxis using human clinical samples (99)(100)(101)(102). Our and other groups recently reported the reconstitution of lymphocyte subsets between HLA-haploidentical PTCy-based HSCT (PTCy-haplo) as compared to HLA-identical donor HSCT using conventional GVHD prophylaxis (101,102). These studies demonstrated that the number of T cells was significantly lower in PTCy-haplo than that in HLA-identical HSCT in the early phase, which was due to slower CD4 + Tcons reconstitution.…”

Section: The Effect Of Ptcy On Treg Homeostasis After Hsctmentioning

confidence: 99%

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Ikegawa

Matsuoka

2021

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

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

Cited by 9 publications

References 13 publications

Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

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