PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade

Ikegawa, Shuntaro; Meguri, Yusuke; Kondo, Takumi; Sugiura, Hiroyuki; Sando, Yasuhisa; Nakamura, Makoto; Iwamoto, Miki; Maeda, Yoshinobu; Matsuoka, Ken

doi:10.1182/bloodadvances.2019000134

Cited by 26 publications

(23 citation statements)

References 63 publications

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“…Importantly, in the current study, PTCy reduced the percentages of Tregs; however, we did not assess splenic Treg numbers, which is an important indicator of immune function. PTCy can increase Treg number in allogeneic mouse models of GVHD [54], but there are limited data in humanized mice. We have previously observed human Tregs in humanized NSG mice with GVHD [31,38,49,[55][56][57][58]; however, PTCy is the first treatment in our laboratory to impact these cells in this model.…”

Section: Ptcy Reduces Gvhd In a Humanized Mouse Modelmentioning

confidence: 99%

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model

et al. 2021

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Graft-versus-host disease (GVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that develops when donor T cells in the graft become reactive against the host. Post-transplant cyclophosphamide (PTCy) is increasingly used in mismatched allo-HSCT, but how PTCy impacts donor T cells and reduces GVHD is unclear. This study aimed to determine the effect of PTCy on reactive human donor T cells and GVHD development in a preclinical humanized mouse model. Immunodeficient NODscid-IL2Rγ null mice were injected intraperitoneally (i.p.) with 20 × 10 6 human peripheral blood mononuclear cells stained with carboxyfluorescein succinimidyl ester (CFSE) (day 0). Mice were subsequently injected (i.p.) with PTCy (33 mg kg −1 ) (PTCymice) or saline (saline-mice) (days 3 and 4). Mice were assessed for T-cell depletion on day 6 and monitored for GVHD for up to 10 weeks. Flow cytometric analysis of livers at day 6 revealed lower proportions of reactive (CFSE low ) human (h) CD3 + T cells in PTCy-mice compared with saline-mice. Over 10 weeks, PTCy-mice showed reduced weight loss and clinical GVHD, with prolonged survival and reduced histological liver GVHD compared with saline-mice. PTCy-mice also demonstrated increased splenic hCD4 + :hCD8 + T-cell ratios and reduced splenic Tregs (hCD4 + hCD25 + hCD127 lo ) compared with saline-mice. This study demonstrates that PTCy reduces GVHD in a preclinical humanized mouse model. This corresponded to depletion of reactive human donor T cells, but fewer human Tregs.

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Section: Ptcy Reduces Gvhd In a Humanized Mouse Modelmentioning

confidence: 99%

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model

et al. 2021

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“…They found that inhibited PD-1 signaling led to increased and enhanced expansion of CD4 + T cells and unfortunately, Treg cells were unable to support the expansion due to increased apoptosis, resulting in deficiencies in the immune recovery, allowing for development of severe GVHD. Using PTCY on day +3 after transplantation in mice, it was noted that CD4 + T cell populations were decreased with increased Treg populations in the first 2 weeks compared with mice that did not receive PTCY, allowing for a well-balanced immune reconstitution and less GVHD [15]. This study provided insight in how PTCY may be beneficial as a method of GVHD prophylaxis in patients who received prior PD-1 blockade.…”

Section: Acute Gvhd After Transplant In Mds Patientmentioning

confidence: 79%

“…Subsequently, high-dose, single agent post-transplant cyclophosphamide (PTCY) was found to be effective as GVHD prophylaxis and is now standardly used, especially in the setting of haplo-identical [14]. More recently, Ikegawa et al investigated the mechanism of PD-1 blockade in GVHD and how PTCY may impact this process in murine models [15]. They found that inhibited PD-1 signaling led to increased and enhanced expansion of CD4 + T cells and unfortunately, Treg cells were unable to support the expansion due to increased apoptosis, resulting in deficiencies in the immune recovery, allowing for development of severe GVHD.…”

Section: Acute Gvhd After Transplant In Mds Patientmentioning

confidence: 99%

First Report of Severe Acute Graft-Versus-Host Disease After Allogeneic Stem Cell Transplant in a Patient With Myelodysplastic Syndrome Treated With Atezolizumab: Literature Review

et al. 2020

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Checkpoint inhibitors have become a widely used and available immunotherapy option for treating a variety of malignancies, including hematological malignancies. Patients receiving these therapies may go on to receive a curative allogeneic hematopoietic stem cell transplant (allo-HSCT). This presents a clinical challenge as the safety and efficacy of HSCT is not well reported in this subset of patients and residual programmed death-ligand 1 inhibition could potentially enhance allogeneic T-cell responses, improving the graft-versus-tumor effect, but also increasing the incidence and severity of immune complications such as graft-versus-host disease (GVHD). Here, this report includes a detailed literature review summarizing all available data on HSCT outcomes in the setting of using checkpoint inhibitor therapy pre-transplant. Moreover, we report a case of acute GVHD after allo-HSCT in a patient with high-risk myelodysplastic syndrome who received prior atezolizumab therapy, highlighting the importance of further research into this specific population in order to improve transplant-related outcomes.

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“…*P < 0.05, **P < 0.01, ***P < 0.001. (13,32,33). Regulatory T cells (Tregs), as well as transforming growth factor-b (TGF-b) and IL-10, are known to have important inhibitory functions in CD4 + T-cell proliferation (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…As an important component of the immune system, CD4 + T cells play an indispensable role in resisting foreign pathogens and mediate the development of autoimmunity ( 30 , 31 ). Abnormal CD4 + T-cell proliferation has been implicated in the development of various diseases including peripheral T-cell proliferative diseases/lymphomas, inflammatory/infection diseases, graft-versus-host disease and autoimmune diseases ( 13 , 32 , 33 ). Regulatory T cells (Tregs), as well as transforming growth factor-β (TGF-β) and IL-10, are known to have important inhibitory functions in CD4 + T-cell proliferation ( 34 – 36 ).…”

Section: Discussionmentioning

confidence: 99%

Dracocephalum heterophyllum (DH) Exhibits Potent Anti-Proliferative Effects on Autoreactive CD4+ T Cells and Ameliorates the Development of Experimental Autoimmune Uveitis

Bian

Wang

et al. 2020

Front. Immunol.

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Experimental autoimmune uveitis (EAU) is a CD4 + T cell-mediated organ-specific autoimmune disease and has been considered as a model of human autoimmune uveitis. Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. DH suppressed the production of inflammatory cytokines through the recruitment of myeloid-derived suppressor cells (MDSCs) to the liver. However, it remains elusive whether DH can directly regulate CD4 + T cell biology and hence ameliorates the development of CD4 + T cell-mediated autoimmune disease. In the current study, we found that DH extract significantly suppressed the production of pro-inflammatory cytokines by CD4 + T cells. Further study showed that DH didn't affect the activation, differentiation, and apoptosis of CD4 + T cells. Instead, it significantly suppressed the proliferation of conventional CD4 + T cells both in vitro and in vivo. Mechanistic study showed that DH-treated CD4 + T cells were partially arrested at the G2/M phase of the cell cycle because of the enhanced inhibitory phosphorylation of Cdc2 (Tyr15). In addition, we demonstrated that treatment with DH significantly ameliorated EAU in mice through suppressing the proliferation of autoreactive antigen specific CD4 + T cells. Taken together, the current study indicates that DH-mediated suppression of CD4 + T cell proliferation may provide a promising therapeutic strategy for treating CD4 + T cell-mediated diseases.

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PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade

Abstract: Key Points PD-1 blockade exacerbated GVHD by altering the homeostasis of Tregs and effector T cells after HSCT. PTCy ameliorated GVHD after PD-1 blockade by restoring the homeostatic balance of T-cell subsets.

Cited by 26 publications

References 63 publications

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model

First Report of Severe Acute Graft-Versus-Host Disease After Allogeneic Stem Cell Transplant in a Patient With Myelodysplastic Syndrome Treated With Atezolizumab: Literature Review

Dracocephalum heterophyllum (DH) Exhibits Potent Anti-Proliferative Effects on Autoreactive CD4+ T Cells and Ameliorates the Development of Experimental Autoimmune Uveitis

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