Immunomodulation of Delayed-Type Hypersensitivity Responses by Mesenchymal Stem Cells Is Associated with Bystander T Cell Apoptosis in the Draining Lymph Node

Lim, Jong Hyung; Kim, Jung-Sik; Yoon, Ina; Shin, Juyeon; Nam, Hyun-Yeol; Yang, Seung Ha; Kim, Sang Joon; Park, Chung Gyu

doi:10.4049/jimmunol.0902723

Cited by 47 publications

(42 citation statements)

References 36 publications

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“…As haptens are not immunogenic by themselves but able to elicit immune responses only when binding to a protein, they have been frequently used as the most suitable allergen substitute to reproduce human disease. Lim and colleagues reported that IV infused BMSCs alleviated the murine CHS through the NO-mediated induction of activated T cell apoptosis in the dLNs [70]. In addition, Su et al demonstrated that IV administration of human gingiva-derived MSCs (hGMSCs) significantly attenuated the symptoms of murine CHS to a similar extent in the BMSCs-injected group.…”

Section: Preclinical and Clinical Studies Of Mscs In Inflammatory mentioning

confidence: 99%

Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action

Shin

Kim

Choi

et al. 2017

IJMS

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Inflammatory skin disorders that cause serious deterioration of the quality of life have become one of the major public concerns. Despite their significance, there is no fundamental cure to date. Mesenchymal stem cells (MSCs) possess unique immunomodulatory properties which make them a promising tool for the treatment of various inflammatory diseases. Our recent preclinical and clinical studies have shown that MSCs can be successfully used for the treatment of atopic dermatitis (AD), one of the major inflammatory skin diseases. This observation along with similar reports from other groups revealed the efficacy and underlying mechanisms of MSCs in inflammatory dermatosis. In addition, it has been proposed that cell priming or gene transduction can be novel strategies for the development of next-generation high-efficacy MSCs for treating inflammatory skin diseases. We discuss here existing evidence that demonstrates the regulatory properties of MSCs on immune responses under inflammatory conditions.

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Section: Preclinical and Clinical Studies Of Mscs In Inflammatory mentioning

confidence: 99%

Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action

Shin

Kim

Choi

et al. 2017

IJMS

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“…The abundance of mediators identified to date suggests that MSCs exploit different immunosuppressive mechanisms under different disease conditions. MSC therapy has been successful in a range of disease models and some clinical conditions known to be associated with damaging effector T-cell responses or failure of T reg -mediated counter-regulation or both [4,6,8,11,22,25-28]. Overall, it is now very well established that MSCs exert diverse and potent modulatory effects on the T-cell compartment of the immune system, most of which are suppressive in nature and of potential therapeutic value.…”

Section: An Introduction To Mesenchymal Stem Cell Modulation Of T Celmentioning

confidence: 99%

Mesenchymal stem cell effects on T-cell effector pathways

et al. 2011

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Mesenchymal stem (stromal) cells (MSCs) are rare, multipotent progenitor cells that can be isolated and expanded from bone marrow and other tissues. Strikingly, MSCs modulate the functions of immune cells, including T cells, B cells, natural killer cells, monocyte/macrophages, dendritic cells, and neutrophils. T cells, activated to perform a range of different effector functions, are the primary mediators of many autoimmune and inflammatory diseases as well as of transplant rejection and graft-versus-host disease. Well-defined T-cell effector phenotypes include the CD4+ (T helper cell) subsets Th1, Th2, and Th17 cells and cytotoxic T lymphocytes derived from antigen-specific activation of naïve CD8+ precursors. In addition, naturally occurring and induced regulatory T cells (Treg) represent CD4+ and CD8+ T-cell phenotypes that potently suppress effector T cells to prevent autoimmunity, maintain self-tolerance, and limit inflammatory tissue injury. Many immune-mediated diseases entail an imbalance between Treg and effector T cells of one or more phenotypes. MSCs broadly suppress T-cell activation and proliferation in vitro via a plethora of soluble and cell contact-dependent mediators. These mediators may act directly upon T cells or indirectly via modulation of antigen-presenting cells and other accessory cells. MSC administration has also been shown to be variably associated with beneficial effects in autoimmune and transplant models as well as in several human clinical trials. In a small number of studies, however, MSC administration has been found to aggravate T cell-mediated tissue injury. The multiple effects of MSCs on cellular immunity may reflect their diverse influences on the different T-cell effector subpopulations and their capacity to specifically protect or induce Treg populations. In this review, we focus on findings from the recent literature in which specific modulatory effects of MSCs on one or more individual effector T-cell subsets and Treg phenotypes have been examined in vitro, in relevant animal models of in vivo immunological disease, and in human subjects. We conclude that MSCs have the potential to directly or indirectly inhibit disease-associated Th1, Th2, and Th17 cells as well as cytotoxic T lymphocytes but that many key questions regarding the potency, specificity, mechanistic basis, and predictable therapeutic value of these modulatory effects remain unanswered.

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“…Recently, we published that small, but significant numbers of mouse MSCs infused i.v. to the mice localized at the cortical area of the lymph nodes, in particular, in the draining lymph nodes and induced apoptosis of the activated T cells [27]. In those studies, we found that some of infused MSCs directly contact T cells, dendritic cells, B cells, and possibly Treg cells, but they only exerted apoptotic effects on the activated T cells.…”

Section: Discussionmentioning

confidence: 92%

Murine Mesenchymal Stem Cells Suppress T Lymphocyte Activation Through IL-2 Receptor α (CD25) Cleavage by Producing Matrix Metalloproteinases

Park

Shin

Kim

et al. 2010

Stem Cell Rev and Rep

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Mesenchymal stem cells (MSCs) are multipotent, non-hematopoietic stem cells that exhibit the capacity to inhibit the proliferation of a variety of immune cells. However, the underlying mechanisms of the immunosuppressive effects of MSCs are still obscure. Therefore, we attempted to identify the mechanisms underlying immunosuppression toward the activated T lymphocytes by MSCs in a murine model. In particular, we aimed to find possible factors derived from MSCs that drive this phenomenon. We found that T lymphocytes incubated with conditioned media of MSCs (MSC CM) entered into apoptosis and were subjected to cell cycle arrest during the course of activation, and these phenomena were accompanied by the reduction of IL-2 production. Specifically, matrix metalloproteinases (MMPs) derived from MSCs caused cleavage of IL-2 receptor α (CD25) from the surface of activated T cells, and as a consequence, IL-2 signaling in response to engagement of the IL-2 receptor (IL-2R) was downregulated. The inhibition of MMP activity in the MSC CM by GM6001 abrogated CD25 cleavage and restored IL-2 production from the activated splenocytes. However, the blockade of MMP activity could not fully restore the proliferative response and apoptosis of T cells altered by MSC CM. In conclusion, MSC-derived MMPs have a significant role in the suppression of IL-2 production through induction of CD25 cleavage and have a partial role in the suppression of T cell proliferation.

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Immunomodulation of Delayed-Type Hypersensitivity Responses by Mesenchymal Stem Cells Is Associated with Bystander T Cell Apoptosis in the Draining Lymph Node

Abstract: Material

Cited by 47 publications

References 36 publications

Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action

Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action

Mesenchymal stem cell effects on T-cell effector pathways

Murine Mesenchymal Stem Cells Suppress T Lymphocyte Activation Through IL-2 Receptor α (CD25) Cleavage by Producing Matrix Metalloproteinases

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