Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells

Riegel, Christin; Boeld, Tina J.; Doser, Kristina; Huber, Elisabeth; Hoffmann, Petra; Edinger, Matthias

doi:10.1038/s41375-019-0625-3

Cited by 38 publications

(39 citation statements)

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“…Currently, the application of donor regulatory T cells ameliorates the clinical and histologic symptoms of aGVHD and significantly enhances survival. It prevents aGVHD and it is effective for the treatment of life-threatening complications [31]. The cumulative incidences of EBV and CMV infections were significantly higher in the AD than in the MSD group (all P < 0.001).…”

Section: Discussionmentioning

confidence: 97%

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Alternative donor peripheral blood stem cell transplantation for the treatment of high-risk refractory and/or relapsed childhood acute leukemia: a randomized trial

Zhang

Zhou

et al. 2020

Exp Hematol Oncol

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Background: The high-risk refractory and/or relapsed (R/R) childhood acute leukemia prognosis is poor, and allogeneic stem cell transplantation (allo-HSCT) is the most prudent treatment modality. However, there are limited matched sibling donors (MSDs), and alternative donors (ADs) are the main source for allo-HSCT. Thus, we evaluated the clinical efficacy of AD peripheral allo-HSCT for treating high-risk R/R childhood acute leukemia. Methods: We assessed 111 children who underwent allo-HSCT at the Affiliated Cancer Hospital of Zhengzhou University between October 2006 and July 2019. The patients were divided in the MSD and AD groups, and their clinical characteristics, complications, and survival rates were compared. Results: The cumulative incidences of Epstein-Barr virus and cytomegalovirus infections were significantly higher in the AD than in the MSD group (P < 0.001); however, the recurrence and mortality rates were significantly higher in the MSD than in the AD group (P < 0.05). Furthermore, the 5-year disease-free (DFS) (65.2% vs. 43.3%, P = 0.033) and overall survival (OS) rates (71.6% vs. 53.8%, P = 0.053) were significantly higher in the AD than in the MSD group. In the AD group, the grade II-IV acute graft-versus-host disease (aGVHD), donor-recipient ABO compatibility, conditioning regimen, and CMV infection affected the 5-year OS. The grade II-IV aGVHD also affected the 5-year DFS; however, only the donor-recipient ABO compatibility affected the 5-year DFS. The donor MSD (HR: 2.035, 95% confidence interval [CI] 1.057-3.920, P = 0.034) and the grade II-IV aGVHD (HR: 2.914, 95% CI 1.261-6.736, P = 0.012) affected the 5-year DFS of childhood acute leukemia after allo-HSCT, and the grade II-IV aGVHD (HR: 3.016, 95% CI 1.217-7.473, P = 0.017) affected the 5-year OS. Moreover, the donor source (HR: 2.836, 95% CI 1.179-6.823, P = 0.020) and grade II-IV aGVHD (HR: 3.731, 95% CI 1.332-10.454, P = 0.012) were independent predictors of the 5-year DFS, while the latter (HR: 3.524, 95% CI 1.310-10.988, P = 0.030) was an independent predictor of the 5-year OS. Conclusions: AD-PBSCT was effective for high-risk R/R childhood leukemia and may have better clinical outcomes than MSD-PBSCT; thus, it can be used as first-line treatment for high-risk R/R childhood leukemia.

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Section: Discussionmentioning

confidence: 97%

“…Transplantation related complications are the main determinants of survival; particularly, GVHD may be one of the most important factors affecting survival and prognosis [29][30][31]. We compared the occurrence of complications between the AD and MSD groups.…”

Section: Discussionmentioning

confidence: 99%

Alternative donor peripheral blood stem cell transplantation for the treatment of high-risk refractory and/or relapsed childhood acute leukemia: a randomized trial

Zhang

Zhou

et al. 2020

Exp Hematol Oncol

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“…Treg populations including natural Tregs (nTregs) and iTregs ameliorate GvHD severity by suppressing cytotoxic T cells (15,19,50), and Treg deficiency after allo-HCT has been associated with severe aGvHD (51). Previous studies have shown that β2-AR signaling induces Treg immunosuppressive functions through an increase in CTLA-4 expression and a decrease in IL-2 levels (34,35).…”

Section: Discussionmentioning

confidence: 99%

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Mohammadpour¹,

Sarow²,

MacDonald³

et al. 2020

JCI Insight

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warmer, thermoneutral temperature (TT). Housing mice at TT substantially reduces norepinephrine and β-AR signaling on immune cells (22). Treatment of allo-HCT mice housed at ST with the pan-beta blocker propranolol increased aGvHD severity, indicating that β-AR signaling is protective against aGvHD (22). Furthermore, we demonstrated that blockade of recipient β2-ARs enhanced the GvT effect by modulating antigen presenting cells (23). It was critical to continue to define the role of T cell β2-AR signaling, especially CD4 + T cell differentiation. In addition, the detailed mechanisms of β2-AR signaling and its downstream effects on immunomodulation after allo-HCT remained incompletely understood.Adrenergic receptors (ARs) are G protein-coupled receptors, classified into 2 general classes: α-ARs and β-ARs. The α1-AR is primarily expressed on endothelial cells, and the α2-AR is more ubiquitously expressed. β1-ARs and β3-ARs are primarily expressed in cardiac and adipose tissues, respectively, while β2-ARs are extensively distributed especially in the respiratory tract (24, 25) and on immune cells (26,27). Emerging studies reinforce an inhibitory role of β2-AR signaling on T cell function, especially CD8 + T cells, in preclinical and clinical tumor models (27,28). The β2-AR is activated by catecholamines (norepinephrine and epinephrine), released by the sympathetic nervous system (27, 29) and splenic tyrosine hydroxylase-expressing cells (30). This β2-AR-mediated regulation affects T cell antitumor functions (28), DC antigen presentation (23), B cell expression of costimulatory molecules (31, 32), and myeloid-derived suppressor cell (MDSC) immunosuppression ( 26).Thus, we focused on the role of β2-AR signaling on immune cell development and pathways during aGvHD. We asked whether β2-AR expression by allogeneic donor T cells modulates aGvHD pathology and how this modulation occurs. Using major histocompatibility complex (MHC) and minor histocompatibility antigen (miHA) mismatched HCT murine models, and a humanized NOD-scid IL-2Rγ -/-(NSG) model of aGvHD, we demonstrate that β2-AR expression by allogeneic T cells regulates the differentiation of CD4 + T cells from Th1/Th17 to a Th2/Treg phenotype, ameliorating aGvHD without compromising GvT. These data lead us to propose that selective β2-AR agonists may serve as potential therapeutic agents to attenuate aGvHD while preserving the GvT effect.

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“…However, increased "priming" of all T-cell subsets reversed in patients with severe GVHD with typical lymphopenia, who received more intensive immunosuppressive therapy (Murase et al, 2014). Based on the characteristics of Tregs, adoptive Tregs transfer has prevented and treated GVHD (Mancusi et al, 2019;Riegel et al, 2020).…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

Man

Yao

Yang

et al. 2021

Front. Cell Dev. Biol.

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Self-renewal and multidirectional differentiation of hematopoietic stem cells (HSCs) are strictly regulated by numerous cellular components and cytokines in the bone marrow (BM) microenvironment. Several cell types that regulate HSC niche have been identified, including both non-hematopoietic cells and HSC-derived cells. Specific changes in the niche composition can result in hematological malignancies. Furthermore, processes such as homing, proliferation, and differentiation of HSCs are strongly controlled by the BM niche and have been reported to be related to the success of hematopoietic stem cell transplantation (HSCT). Single-cell sequencing and in vivo imaging are powerful techniques to study BM microenvironment in hematological malignancies and after HSCT. In this review, we discuss how different components of the BM niche, particularly non-hematopoietic and hematopoietic cells, regulate normal hematopoiesis, and changes in the BM niche in leukemia and after HSCT. We believe that this comprehensive review will provide clues for further research on improving HSCT efficiency and exploring potential therapeutic targets for leukemia.

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Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells

Cited by 38 publications

References 61 publications

Alternative donor peripheral blood stem cell transplantation for the treatment of high-risk refractory and/or relapsed childhood acute leukemia: a randomized trial

Alternative donor peripheral blood stem cell transplantation for the treatment of high-risk refractory and/or relapsed childhood acute leukemia: a randomized trial

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

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