Lower incidence of acute GVHD is associated with the rapid recovery of CD4+CD25+CD45RA+ regulatory T cells in patients who received haploidentical allografts from NIMA-mismatched donors: A retrospective (development) and prospective (validation) cohort-based study

Wang, Yu; Zhao, Xiang-Yu; Xu, Lei; Zhang, Xiao-Hui; Han, Wei; Chen, Huan; Wang, Feng-Rong; Mo, Xiao‐Dong; Zhang, Yuanyuan; Zhao, Xinyang; Kong, Yuan; Liua, Kai-Yan; Huang, Xiao‐Jun; Yu, Xue-Zhong; Chang, Ying‐Jun

doi:10.1080/2162402x.2016.1242546

Cited by 11 publications

(4 citation statements)

References 38 publications

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“…Our recent study also confirmed the Treg-dependent mechanism in lower GVHD incidence after NIMA-exposed donor HCT. 18 Impressively, the joint use of low-dose PTCy and ATG was safe in terms of engraftment, relapse prevention, or other adverse effects. Low-dose PTCy along with ATG and G-CSF did not influence haematopoietic recovery.…”

Section: Discussionmentioning

confidence: 94%

“…15 Meanwhile, in G-CSF/ATG protocol, rapid reconstitution of Tregs has been demonstrated after non-inherited maternal-antigen (NIMA)mismatched donor HCT compared with non-inherited paternal-antigen (NIPA)-mismatched donor transplant, which translated into a lower incidence of acute GVHD after NIMAexposed donor HCT. 18 Based on the above findings, we postulate that lower-dose of PTCy could be sufficient for tolerance induction to warrant alleviating GVHD without compromising graft-vs.-leukemia (GVL) effect.…”

Section: Introductionmentioning

confidence: 95%

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Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes

et al. 2017

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Use of high-dose, post-transplant cyclophosphamide (PTCy) results in low rates of graft-versus-host-disease (GVHD) and favorable immune reconstitution, although with higher rates of relapse and somewhat high rates of graft failure. We hypothesized that permissible dose reduction of PTCy might be feasible. The current study attempts to establish a murine model and focus on regulatory T cells (Tregs) to clarify the immunological mechanisms for GVHD prevention by low-dose PTCy. In addition, a prospective, clinical cohort study in haploidentical, T-cell replete transplantation is initiated to support the rational. We found that acute GVHD could be alleviated by low-dose PTCy and could be further mitigated after the combined use of low-dose PTCy and antithymocyte globulin (ATG) in mice. Flow-cytometric analyses in mice showed that low-dose PTCy could increase the number of Tregs and the effect on Tregs is significantly prominent with the combined use of low-dose PTCy and ATG. In the clinical cohort study, the cumulative incidence of grades II-IV acute GVHD in combined treatment cohort with low-dose PTCy and ATG/granulocyte colony-stimulating factor (G-CSF) (17%; 95% CI, 5-29%) was significantly lower than both that in matched-pair cohort (33%; 95% CI, 25-41%; P = 0.04) and that in historical cohort (56%; 95% CI, 42-70%; P < 0.001). In-vivo immune reconstitution analysis showed that low-dose PTCy could facilitate suppressive Tregs reconstitution. In conclusion, low-dose PTCy is sufficient for GVHD abrogation under lymphopenic situation and can enhance the protective effect of ATG/G-CSF on GVHD. Intensified conditioning followed by low-dose PTCy might be a feasible option for patients undergoing haploidentical transplantation.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 95%

Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes

et al. 2017

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“…Several studies have examined the relationships of immune components with outcomes in patients with hematological malignancies. [ 5 9 14 42 43 44 45 ] Fisher et al . [ 46 ] conducted a meta-analysis showing that high levels of regulatory T cells in the grafts were associated with improved OS, with a significant reduction in TRM and a reduced risk of acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

Relationship of Cell Compositions in Allografts with Outcomes after Haploidentical Transplantation for Acquired Severe Aplastic Anemia

Cao

Zhang

et al. 2018

Chinese Medical Journal

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Background:The dose of certain cell types in allografts affects engraftment kinetics and clinical outcomes after allogeneic stem cell transplantation (SCT). Hence, the present study investigated the association of cell compositions in allografts with outcomes after unmanipulated haploidentical SCT (haplo-SCT) for patients with acquired severe aplastic anemia (SAA).Methods:A total of 131 patients with SAA who underwent haplo-SCT were retrospectively enrolled. Cell subsets in allografts were determined using flow cytometry. To analyze the association of cellular compositions and outcomes, Mann–Whitney U nonparametric tests were conducted for patient age, sex, weight, human leukocyte antigen mismatched loci, ABO-matched status, patient ABO blood type, donor-recipient sex match, donor-recipient relationship, and each graft component. Multivariate analysis was performed using logistic regression to determine independent influence factors involving dichotomous variables selected from the univariate analysis.Results:A total of 126 patients (97.7%) achieved neutrophil engraftment, and 121 patients (95.7%) achieved platelet engraftment. At 100 days after transplantation, the cumulative incidence of II–IV acute graft-versus-host disease (GVHD) was 32.6%. After a median follow-up of 842 (range: 124–4110) days for surviving patients, the cumulative incidence of total chronic GVHD at 3 years after transplantation was 33.7%. The probability of overall survival at 3 years was 83.0%. Multivariate analysis showed that higher total doses of CD14+ (P = 0.018) and CD34+ cells (P < 0.001) were associated with a successful platelet engraftment. A successful platelet was associated with superior survival (P < 0.001). No correlation of other cell components with outcomes was observed.Conclusions:These results provide evidence and explain that higher doses of CD34+ and CD14+ cells in haploidentical allografts positively affect platelet engraftment, contributing to superior survival for patients with SAA.

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“…Moreover, in the Baltimore experience with a cohort of patients undergoing MAC haplo-HCT using PTCy, MMF, and tacrolimus-based GVHD prophylaxis, Tregs achieved normal donor levels at all time-points examined (day +30, +90, +180, and +365) (181). Finally, in haplo-HCT using the GIAC protocol, patients with a higher day +30 percentage of naive Treg, defined as CD4 + CD25 + CD45RA + , had a significantly lower incidence of grades II-IV acute GVHD (191). This highlights the importance of reaching a satisfactory Treg reconstitution for the achievement of immune tolerance after haplo-HCT.…”

Section: Regulatory T (Treg) Cellsmentioning

confidence: 88%

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem-or immune cells for the recipient, haplo-HCT represents a unique platform for cell-and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality.

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Lower incidence of acute GVHD is associated with the rapid recovery of CD4⁺CD25⁺CD45RA⁺ regulatory T cells in patients who received haploidentical allografts from NIMA-mismatched donors: A retrospective (development) and prospective (validation) cohort-based study

Cited by 11 publications

References 38 publications

Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes

Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes

Relationship of Cell Compositions in Allografts with Outcomes after Haploidentical Transplantation for Acquired Severe Aplastic Anemia

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

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