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Association between CD34(+) and CD3(+) T-cells in allogeneic grafts and acute graft-versus-host disease in children undergoing allogeneic hematopoietic stem cell transplantation: A single-center study
Yao, D., Li, B., Chu, X., Pan, J., Meng, L., Hu, Y., Gao, L., Li, J., Tian, Y., Hu, S.
Transplant immunology. 2022;77:101779
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We examined the association between the composition of the cell subsets present in allogeneic grafts (allografts) and the occurrence and severity of aGVHD in pediatric patients. METHODS We retrospectively analyzed 80 consecutive pediatric patients undergoing allo-HSCT at our center. RESULTS Both univariate and multivariate analyses showed that the number of CD34(+) and CD3(+) T-cells in allografts were the two highest risk factors associated with II-IV aGVHD. Using receiver operating characteristic analysis, the cutoff levels of the allo-HSCT cell doses were used to divide the recipients into low-dose and high-dose groups. The 100-day cumulative incidence of II-IV aGVHD in the high-dose CD34(+) and CD3(+) T-cells group was significantly higher than that of the low-dose group (CD34(+): 57% vs. 29%, p = 0.009; CD3(+): 63% vs. 18%, p < 0.001). No other clinical factors or cell subsets correlated with aGVHD incidence. CONCLUSIONS Our analysis indicates that the CD34(+) and CD3(+) T-cell numbers in the allografts could be the risk factors for the development of severe aGVHD (level II-IV). Further studies should aim to optimize the critical number of CD34(+) and CD3(+) T-cells to reduce the risk of severe aGVHD occurrence in pediatric patients.
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Cytotoxicity of Donor Natural Killer Cells to Allo-Reactive T Cells Are Related With Acute Graft-vs.-Host-Disease Following Allogeneic Stem Cell Transplantation
Sheng, L., Mu, Q., Wu, X., Yang, S., Zhu, H., Wang, J., Lai, Y., Wu, H., Sun, Y., Hu, Y., et al
Frontiers in immunology. 2020;11:1534
Abstract
Objectives: The mechanism and immunoregulatory role of human natural killer (NK) cells in acute graft-vs.-host-disease (aGVHD) remains unclear. This study quantitatively analyzed the cytotoxicity of donor NK cells toward allo-reactive T cells, and investigated their relationship with acute GVHD (aGVHD). Methods: We evaluated NK dose, subgroup, and receptor expression in allografts from 98 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A CD107a degranulating assay was used as a quantitative detection method for the cytotoxic function of donor NK cells to allo-reactive T cells. In antibody-blocking assay, NK cells were pre-treated with anti-DNAM-1(CD226), anti-NKG2D, anti-NKP46, or anti-NKG-2A monoclonal antibodies (mAbs) before the degranulating assay. Results: NK cells in allografts effectively inhibited auto-T cell proliferation following alloantigen stimulation, selectively killing alloantigen activated T cells. NKG2A(-) NK cell subgroups showed higher levels of CD107a degranulation toward activated T cells, when compared with NKG2A(-) subgroups. Blocking NKG2D or CD226 (DNAM-1) led to significant reductions in degranulation, whereas NKG2A block resulted in increased NK degranulation. Donor NK cells in the aGVHD group expressed lower levels of NKG2D and CD226, higher levels of NKG2A, and showed higher CD107a degranulation levels when compared with NK cells in the non-aGVHD group. Using univariate analysis, higher NK degranulation activities in allografts (CD107a(high)) were correlated with a decreased risk in grade I-IV aGVHD (hazard risk [HR] = 0.294; P < 0.0001), grade III-IV aGVHD (HR = 0.102; P < 0.0001), and relapse (HR = 0.157; P = 0.015), and improved overall survival (HR = 0.355; P = 0.028) after allo-HSCT. Multivariate analyses showed that higher NK degranulation activities (CD107a(high)) in allografts were independent risk factors for grades, I-IV aGVHD (HR = 0.357; P = 0.002), and grades III-IV aGVHD (HR = 0.13; P = 0.009). Conclusions: These findings reveal that the degranulation activity of NK in allografts toward allo-activated T cells was associated with the occurrence and the severity of aGVHD, after allogeneic stem cell transplantation. This suggested that cytotoxicity of donor NK cells to allo-reactive T cells have important roles in aGVHD regulation.
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Risk Factors for Graft-Versus-Host Disease After Transplantation of Hematopoietic Stem Cells from Unrelated Donors in the China Marrow Donor Program
Yang, F., Lu, D., Hu, Y., Huang, X., Huang, H., Chen, J., Wu, D., Wang, J., Wang, C., Han, M., et al
Annals of Transplantation. 2017;22:384-401
Abstract
BACKGROUND We identified risk factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) in recipients after hematopoietic stem cell transplantation (HSCT) from unrelated donors in the China Marrow Donor Program (CMDP). MATERIAL AND METHODS We analyzed follow-up clinical information from 1824 patients who underwent HSCT between 2001 and 2010. RESULTS The incidence of aGVHD and cGVHD after transplantation was 49.29% and 27.3%, respectively. aGVHD incidence decreased as HLA matching increased (p<0.001). Incidence of aGVHD and cGVHD was higher in 2 HLA-A locus donor/recipient groups (02: 01/02: 06 and 02: 01/02: 07; p<=0.022). aGVHD incidence was associated with patient age, absence of rabbit anti-thymocyte globulin (ATG) pretreatment, and disease status (p<=0.040). aGVHD appeared to be a risk factor for cGVHD, and total body irradiation (TBI) was also associated with cGVHD. Patients with cGVHD after transplantation had a higher survival rate than patients without cGVHD (p<0.001), which may be due to reduced relapse rates. Survival was also associated with ATG prophylaxis and disease status. CONCLUSIONS The incidence of GVHD after HSCT from unrelated donors in the Chinese population is similar to the results reported from other countries. A high degree of HLA matching, a conditioning regimen without TBI, and the use of ATG may reduce the incidence of aGVHD.
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Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study
Tan, Y., Xiao, H., Wu, D., Luo, Y., Lan, J., Liu, Q., Yu, K., Shi, J., He, J., Zheng, W., et al
Oncoimmunology. 2017;6(3):e1277307
Abstract
Acute graft versus host disease (aGVHD) remains a major problem after allogeneic hematopoietic stem cell transplantation. Standard frontline therapy for aGVHD involves corticosteroids. However, fewer than half of patients have a lasting complete response. The long-term mortality rate of steroid-refractory aGVHD (SR-aGVHD) remains around 70%. To date, no consensus has been reached regarding the optimal salvage treatment for SR-aGVHD. We performed the first prospective, multi-center clinical trial to assess the efficacy and safety of a novel approach to treat severe (grades III-IV) SR-aGVHD with the combination of basiliximab and etanercept. Sixty-five patients with severe SR-aGVHD from six centers were included. The median number of basiliximab infusions was 4 (range 2-11) and of etanercept was 9 (range 2-12). At day 28 after starting the combination treatment, overall response (complete and partial response: CR+PR) to second-line treatment was 90.8% with 75.4% being CR. The incidences of CR per organ were 100%, 73.8%, and 79.7% for skin, liver, and gut involvement, respectively. Patients >30-y old (p = 0.043, RR = 3.169), development of grades III-IV liver aGVHD (p = 0.007, RR = 5.034) and cytomegalovirus (CMV) reactivation (p = 0.035, RR = 4.02) were independent predictors for incomplete response. Combined treatment with basiliximab and etanercept resulted in improved CR to visceral aGVHD and significantly superior 2-y overall survival (54.7% vs. 14.8%, p <0.001) compared with classical salvage treatments. Our data suggest that the combination of basiliximab and etanercept may constitute a promising new treatment option for SR-aGVHD.
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Reduction of Foxp3+ T cell subsets involved in incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Hu, Y., Cui, Q., Ye, Y., Luo, Y., Tan, Y., Shi, J., Huang, H.
Hematological Oncology. 2017;35(1):118-124
Abstract
Foxp3+ T cells (CD4+ Tregs and CD8+ Treg) have been demonstrated to play roles in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). We have found that Foxp3+ gammadeltaTCR+ Treg cells (gammadeltaTregs) exerted regulatory functions. In the current study, patients were recruited and divided as non-cGVHD, limited cGVHD and extensive cGVHD groups. Healthy volunteers were recruited as healthy group. Treg cells were evaluated by flow cytometry. Serum cytokine levels of IL-2, tumour necrosis factor-alpha, interferon-gamma and transforming growth factor-beta1 (TGF-beta1) were evaluated by ELISA. The results showed that percentages of CD4+ Tregs, CD8+ Tregs and gammadeltaTregs were all significantly increased in non-cGVHD group compared with those in healthy group, limited cGVHD group and extensive cGVHD group. Moreover, compared with extensive cGVHD group, percentages of these three types of Tregs were significantly increased in limited cGVHD group. The levels of TGF-beta1 increased dramatically in non-cGVHD group compared with other groups. Spearman's correlation analysis revealed that the increased levels of TGF-beta1 and IL-2 were positively associated with increased Treg subsets, indicating that TGF-beta1 and IL-2 participated in the expansion process of Foxp3+ Tregs in vivo. Our findings support that increasing the number of Tregs following allo-HSCT would be a preferential strategy for controlling cGVHD. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
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Regulatory B cells promote graft-versus-host disease prevention and maintain graft-versus-leukemia activity following allogeneic bone marrow transplantation
Hu, Y., He, G. L., Zhao, X. Y., Zhao, X. S., Wang, Y., Xu, L. P., Zhang, X. H., Yu, X. Z., Liu, K. Y., Chang, Y. J., et al
Oncoimmunology. 2017;6(3):e1284721
Abstract
Regulatory B cells (Bregs) are involved in the pathogenesis of graft-versus-host disease (GVHD). However, whether Bregs can alleviate acute GVHD without compromising graft-versus-leukemia (GVL) effects remains unclear. Here, we evaluated the role of Bregs in acute GVHD and GVL activity in both a mouse model and a clinical cohort study. In the acute GVHD mouse model, co-transplantation of Bregs prevents onset through inhibiting Th1 and Th17 differentiation and expanding regulatory T cells. In the GVL mouse model, Bregs contributed to the suppression of acute GVHD but had no adverse effect on GVL activity. In the clinical cohort study, a higher dose of Bregs in allografts was associated with a lower cumulative incidence of acute GVHD but not with increased risk of relapse. Our data demonstrate that Bregs can prevent acute GVHD and maintain GVL effects and suggest that Bregs have potential as a novel strategy for acute GVHD alleviation.