Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation

Tatara, Raine; Ozaki, Katsutoshi; Kikuchi, Yuji; Hatanaka, Keiko; Oh, Iekuni; Meguro, Akiko; Matsu, Haruko; Sato, Kazuya; Ozawa, Keiya

doi:10.3109/14653249.2010.542456

Cited by 86 publications

(64 citation statements)

References 44 publications

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“…A large body of data convincingly show that autologous and allogeneic MSCs modulate T-cell proliferation, activation, and function both in vitro and in vivo (Di Nicola et al 2002;Glennie et al 2005;English et al 2007;Asari et al 2009;Ding et al 2009;English and Mahon 2011). Moreover, in vitro assays have also confirmed the capacity for MSCs to inhibit Th17 cell differentiation (Duffy et al 2011;Tatara et al 2011) or to shift the T helper cell balance in favor of a more anti-inflammatory phenotype (Batten et al 2006;Bai et al 2009;English et al 2009;Fiorina et al 2009;Ghannam et al 2010). The mechanisms used by MSCs in mediating these effects vary between in vitro and in vivo models.…”

Section: Mesenchymal Stromal Cell Suppression Of Allogeneic T-cell Rementioning

confidence: 95%

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Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

English

Wood

2013

Cold Spring Harbor Perspectives in Medicine

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Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cellbased immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.

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Section: Mesenchymal Stromal Cell Suppression Of Allogeneic T-cell Rementioning

confidence: 95%

“…IDO and PGE-2 have been implicated in MSC inhibition of Th17 differentiation (Duffy et al 2011;Tatara et al 2011). In the case of PGE-2, the steps involved in the process require contactdependent COX-2 induction of PGE-2 and direct inhibition through EP4 (Duffy et al 2011).…”

Section: Mesenchymal Stromal Cell Suppression Of Allogeneic T-cell Rementioning

confidence: 99%

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

English

Wood

2013

Cold Spring Harbor Perspectives in Medicine

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“…However, at lower ratios (i.e., 1:10), differences in IL-10 induction between MAPCs and MSCs were not apparent (data not shown). Although IL-10 induction and Th1 cytokine suppression are regarded as consensus properties for MSCs, suppression of Th17 cells remains more contentious, with discordant reports proposing that MSCs can enhance or inhibit Th17 expansion (42)(43)(44)(45)(46)(47)(48). It was suggested that this may reflect the influence of a network of interdependent variables, such as donor, cell type, licensing, T cell activation status, level of contact, and balance in Th17-enhancing (i.e., TGF-b/IL-6) versus inhibitory (e.g., IDO, PGE 2 ) factors (3,41).…”

Section: Discussionmentioning

confidence: 99%

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

Reading

Yang

Sabbah

et al. 2013

The Journal of Immunology

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A major goal of immunotherapy remains the control of pathogenic T cell responses that drive autoimmunity and allograft rejection. Adherent progenitor cells, including mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs), represent attractive immunomodulatory cell therapy candidates currently active in clinical trials. MAPCs can be distinguished from MSCs on the basis of cellular phenotype, size, transcriptional profile, and expansion capacity. However, despite their ongoing evaluation in autoimmune and allogeneic solid organ transplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited. In this study, we used allogeneic islet transplantation as a model indication to assess the ability of clinical-grade MAPCs to control T cell responses that drive immunopathology in human autoimmune disease and allograft rejection. MAPCs suppressed T cell proliferation and Th1 and Th17 cytokine production while increasing secretion of IL-10 and were able to suppress effector functions of bona fide autoreactive T cells from individuals with type 1 diabetes mellitus, including killing of human islets. Furthermore, MAPCs favored the proliferation of regulatory T cells during homeostatic expansion driven by γ-chain cytokines and exerted a durable, yet reversible, control of T cell function. MAPC suppression required licensing and proceeded via IDO-mediated tryptophan catabolism. Therefore, the common immune modulatory characteristics of clinical-grade MAPCs shown in this study suggest that they can be regarded as an alternative source of adult progenitor cells with similar clinical usefulness to MSCs. Taken collectively, these findings may guide the successful deployment of both MSCs and MAPCs for the amelioration of human autoimmunity and allograft rejection.

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“…55,58 MSC-produced IDO is involved in the induction of regulatory T cells and inhibition of Th17 differentiation. 59,60 MSCderived IDO can also promote differentiation of macrophages toward an M2 phenotype. 61 Activated MSCs can modulate adaptive immune cells through contact-dependent mechanisms.…”

Section: Immune Modulation By Mscsmentioning

confidence: 99%

Stromal cells–are they really useful for GVHD?

Kaipe

Erkers

Sadeghi

et al. 2014

Bone Marrow Transplant

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Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

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Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation

Cited by 86 publications

References 44 publications

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

Stromal cells–are they really useful for GVHD?

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