Combination cell therapy using mesenchymal stem cells and regulatory T cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of Th1/Th2 and Th17/Treg cells in a murine acute graft-versus-host disease model

Lim, Jung Sub; Kim, E.; Im, Keon-Il; Kim, N.; Kim, T.; Sohn, Honglae; Choi, Jeong Won; Cho, S.

doi:10.1016/j.jcyt.2013.01.146

Cited by 6 publications

(8 citation statements)

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“…It has been identified that MSCs mainly control the Th1 response ( 25 ). Among the acute inflammatory molecules, the current study focused on IFN-γ, as this cytokine is a major product of Th1 cells, which reduces the Th2 phenotype and stimulates several key functions to activate macrophages and anti-tumor reaction ( 26 ).…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Nagaya

Mizuno‐Kamiya

Takayama

et al. 2013

Experimental and Therapeutic Medicine

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The mechanisms of immunomodulation by mesenchymal stromal cells remain poorly understood. In this study, the effects of mouse adipose tissue-derived mesenchymal stromal cells (ASCs) on mouse spleen cells alloreactively stimulated by anti-CD3 and anti-CD28 antibody-coated (anti-CD3/CD28) beads were observed. Production of interferon-γ by the anti-CD3/CD28 bead-stimulated spleen cells was significantly suppressed in co-culture with ASCs. However, an augmented intensity of CD69 on the stimulated spleen cells was not suppressed in the presence of ASCs. The immunosuppressive effects of ASCs were partially mediated by one or more soluble factors (26% suppression). However, the ASCs require cell-cell contact in order to maximally exert suppression (88%). The suppressive effect of ASCs mediated by direct cell contact was partially reversed following knockdown of β2 microglobulin, a component of the major histocompatibility complex (MHC) class I molecule, with siRNA. The results of the study demonstrated that ASCs have significant immune modulatory effects on alloreactively stimulated spleen cells. The effects of ASCs on spleen cells are dependent on soluble factor(s) and cell contact, which is mediated by the MHC class I complex on ASCs.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Nagaya

Mizuno‐Kamiya

Takayama

et al. 2013

Experimental and Therapeutic Medicine

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“…The GVHD mouse model was induced by allogenic bone marrow transplantation according to a previous report (21). At the first and fourth days of bone marrow transplantation, 1 3 10 6 BMSCs (BALB/c) were injected via the tail vein into GVHD mice (BALB/c).…”

Section: Bmsc Cytotherapy For Gvhdmentioning

confidence: 99%

“…Mice that were injected with PBS were used as positive control of GVHD. Body weight, survival, and symptoms of mice after bone marrow transplantation were monitored daily for 30 d. The degree of clinical GVHD was assessed by using a previously published scoring system (21). For the histopathologic analysis of GVHD, liver and colon were collected and fixed with 10% formalin after mice were euthanized at the 25th day of bone marrow transplantation.…”

Section: Bmsc Cytotherapy For Gvhdmentioning

confidence: 99%

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Redundant let‐7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis

Liao

Shao

et al. 2018

FASEB j.

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Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

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“…Previous reports suggest that the combination of MSCs and Treg cell therapy have enhanced therapeutic e cacy in transplantation model [43][44][45]. However, the mechanism underlying cross talk between MSC and Treg remains unclear [46].…”

Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

Park

Baek

Kim

et al. 2020

Preprint

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Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysisResults: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3+Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset.Conclusions: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

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Combination cell therapy using mesenchymal stem cells and regulatory T cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of Th1/Th2 and Th17/Treg cells in a murine acute graft-versus-host disease model

Cited by 6 publications

References 0 publications

Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Redundant let‐7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

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