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1.
Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease
Pan, T., Ding, P., Huang, A., Tang, B., Song, K., Sun, G., Wu, Y., Yang, S., Chen, X., Wang, D., et al
Chinese medical journal. 2023
Abstract
BACKGROUND With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking. METHODS A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD. RESULTS The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year (F = 4.684, P = 0.039 and F = 5.583, P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93; P = 0.031). CONCLUSIONS Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.
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2.
Elevated RAP1A expression correlates with the severity of acute GVHD after umbilical cord blood transplantation
Wang, S., Wang, D., Chang, Y., Geng, L., Qiang, P., Sun, G., Tang, B., Zhao, X., Zhou, Z., Liu, H.
Transplant immunology. 2022;:101546
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation. Ras-related protein 1A (RAP1A) has been recently identified as a novel oncoprotein in several human malignancies. However, its specific role in aGVHD remains unclear. OBJECTIVE To study the role of RAP1A in the pathogenesis of aGVHD. MATERIAL AND METHODS Study participants included six patients with grade 2-4 aGVHD, 13 patients with grade 1 aGVHD, 11 patients without aGVHD, and 12 healthy people. The expression level of RAP1A in whole cells was detected by western blot and qRT-PCR. The proportions of CD4(+)CD25(+)FoxP3(+) Treg cells (T regulatory cells) and the expression of RAP1A in Treg cells in peripheral blood mononuclear cells (PBMCs) were detected by flow cytometry and the levels of related cytokines in the serum was detected by cytometric bead array. RESULTS We found the level of RAP1A was higher in patients than in healthy individuals. A negative correlation was noted between RAP1A and the number of Treg cells. In addition, the level of IL-10 in patients with grade 2-4 aGVHD was significantly lower than that in healthy donors, however, the level of TNF-ɑ in patients with grade 2-4 aGVHD was higher. Furthermore, we found a negative correlation between levels of IL-10 and RAP1A, and a positive correlation between TNF-ɑ and RAP1A. CONCLUSION The expression of RAP1A in patients with aGVHD was significantly increased, and shows potential as a target for the prevention and treatment of aGVHD.
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3.
Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation
Ponce, D. M., Politikos, I., Alousi, A., Carpenter, P. A., Milano, F., MacMillan, M. L., Barker, J. N., Horwitz, M. E.
Transplantation and cellular therapy. 2021;27(7):540-544
Abstract
The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.
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Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation
Adachi, M., Yokota, D., Hirata, H., Koyauchi, K., Dohtan, S., Oka, S., Sakamoto, N., Takaba, M., Takemura, T., Nagata, Y., et al
International journal of hematology. 2021
Abstract
The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m(2) on day 1, 3 and 6) to a short-MTX group (10 mg/m(2) on day 1 and 7 mg/m(2) on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p?0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1 year, p?=?0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p?=?0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.
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5.
Role of ATG in patients with hematologic diseases undergoing umbilical cord blood transplantation: A systematic review and meta-analysis
Qin, B. Z., Zhang, C., Zhang, R., Wang, L.
Clinical transplantation. 2020;:e13876
Abstract
The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This systematic review and meta-analysis were conducted to comprehensively evaluate this issue. PubMed, Embase and the Cochrane Library were systematically searched. Clinical studies reporting the impact of ATG- vs. non-ATG-containing conditioning regimens on transplantation outcomes were identified. Twenty-five studies were included. ATG significantly prevented grades II-IV and III-IV acute graft-versus-host disease (GVHD) (11 studies, 5020 patients, HR: 0.49, 95% CI: 0.42 to 0.56, P < 0.001; 5 studies, 5490 patients, HR: 0.60, 95% CI: 0.46 to 0.80, P < 0.001) but not chronic GVHD (8 studies, 5952 patients, HR: 0.78, 95% CI: 0.51 to 1.20, P = 0.266). However, use of ATG was associated with increased transplantation-related mortality and inferior overall survival (9 studies, 4244 patients, HR: 1.79, 95% CI: 1.38 to 2.33, P < 0.001; 8 studies, 5438 patients, HR: 1.96, 95% CI: 1.56 to 2.46, P < 0.001). Our study did not recommend routine use of ATG in UCBT. Individualizing the ATG timing and dose based on patient characteristics to retain the prophylactic effects of ATG on GVHD without compromising the survival of UCBT recipients may be reasonable.
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6.
Effect of graft-versus-host disease on outcomes after pediatric single cord blood transplantation
Kanda, J., Umeda, K., Kato, K., Murata, M., Sugita, J., Adachi, S., Koh, K., Noguchi, M., Goto, H., Yoshida, N., et al
Bone marrow transplantation. 2020
Abstract
The effect of GVHD on transplant outcomes after unrelated cord blood transplantation (UCBT) is not yet fully understood. Pediatric patients aged 0-15 years with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n = 740) were selected from the Japanese registry. Fifty percent of the patients received a UCB unit containing more than 5.0 x 10(7)/kg total nucleated cells. The occurrence of grade III-IV acute GVHD was associated with a higher risk of non-relapse mortality (NRM, hazard ratio [HR] 4.07, P < 0.001) compared with no acute GVHD. Grade I-II acute GVHD was not associated with NRM. The occurrence of grade I-II or grade III-IV acute GVHD was not associated with a relapse risk. These findings showed that grade I-II acute GVHD carried no survival benefit and grade III-IV acute GVHD had an adverse effect (HR 1.68, P = 0.007). The occurrence of limited chronic GVHD was associated with a low risk of overall mortality (HR 0.60, P = 0.045). Severe acute GVHD should be prevented because of its association with high overall mortality and NRM in pediatric single UCBT. Mild acute GVHD provides no overall benefit. Mild chronic GVHD may be beneficial for survival.
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7.
Reconstitution of Circulating Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation: Its Association with the Riboflavin Synthetic Pathway of Gut Microbiota in Cord Blood Transplant Recipients
Konuma, T., Kohara, C., Watanabe, E., Takahashi, S., Ozawa, G., Suzuki, K., Mizukami, M., Nagai, E., Jimbo, K., Kaito, Y., et al
Journal of immunology (Baltimore, Md. : 1950). 2020
Abstract
Mucosal-associated invariant T (MAIT) cells are a type of innate lymphocyte and recognize riboflavin (vitamin B2) synthesis products presented by MHC-related protein 1. We investigated long-term reconstitution of MAIT cells and its association with chronic graft-versus-host disease (cGVHD) in a cross-sectional cohort of 173 adult patients after allogeneic hematopoietic cell transplantation. According to donor source, the number of MAIT cells significantly correlated with time after cord blood transplantation (CBT) but not with time after bone marrow transplantation or peripheral blood stem cell transplantation. The number of MAIT cells was significantly lower in patients with cGVHD compared with patients without cGVHD. We also examined the association between MAIT cell reconstitution and gut microbiota as evaluated by 16S ribosomal sequencing of stool samples 1 mo post-CBT in 27 adult patients undergoing CBT. The diversity of gut microbiota was positively correlated with better MAIT cell reconstitution after CBT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis indicated that amounts of ribB and ribA genes were significantly higher in the microbiomes of patients with subsequent MAIT cell reconstitution after CBT. In conclusion, long-term MAIT cell reconstitution is dependent on the type of donor source. Our data also unveiled an important role for the interaction of circulating MAIT cells with gut microbiota in humans.
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8.
Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation
Goto, T., Murata, M., Nishida, T., Terakura, S., Kamoshita, S., Ishikawa, Y., Ushijima, Y., Adachi, Y., Suzuki, S., Kato, K., et al
Stem cells translational medicine. 2020
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Abstract
Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy not only to prevent graft-vs-host disease (GVHD) but also enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38?days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.
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Different Immune Reconstitution between Cord Blood and Unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease
Yoshida, H., Koike, M., Tada, Y., Nakata, K., Hino, A., Fuji, S., Masaie, H., Oka, C., Higeno, A., Idota, A., et al
International journal of hematology-oncology and stem cell research. 2020;14(1):1-10
Abstract
Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.
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Clinical features of chronic graft-versus-host disease following haploidentical transplantation combined with infusion of a cord blood
Tao, T., Li, Z., Chu, X. L., Zhu, W. J., Xu, Y., Wu, D. P., Ma, X., Xue, S. L.
Stem cells and development. 2019
Abstract
Our previous studies demonstrated promising outcomes after haploidentical donor transplant combined with unrelated umbilical cord blood (haplo-cord-HSCT) for hematological disorders. However, clinical profiling regarding chronic graft-versus-host disease (cGVHD) has not yet been fully described under this protocol. This study analyzed the clinical characteristics of cGVHD among 300 patients with hematological malignancies who received haplo-cord-HSCT between January 2012 and July 2016 at our center. During the follow-up, the 5-year cumulative incidence of cGVHD based on the National Institutes of Health (NIH) consensus criteria was 32.2% (95% confidence interval [CI], 28.7%~35.7%), the 5-year cumulative incidence of moderate to severe cGVHD was 11.4% (95% CI, 9.4%~13.4%). After the multivariate analysis, the cGVHD overall survival (GOS) was associated with relapse, thrombocytopenia, bronchiolitis obliterans syndrome, and steroid-refractory cGVHD. The infused CD34+ cells (≥3.46 x 106/kg) from haploidentical grafts were a protective factor affecting GOS. This study proposed a nomogram for predicting GOS using the aforementioned five variables. The concordance index was 0.877 (95% CI, 0.859~0.895) for the accuracy evaluation of the nomogram. Our results suggested that the 5-year cumulative incidence of NIH-defined cGVHD after haplo-cord-HSCT was 32.2%, and this nomogram may help clinicians select reasonable treatment strategies.