Adoptive T Regulatory Cell Therapy for Tolerance Induction

Cabello-Kindelan, Cecilia; Mackey, Shane; Bayer, Allison L.

doi:10.1007/s40472-015-0058-5

Cited by 10 publications

(7 citation statements)

References 116 publications

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“…Hepatic immunoregulation on ethanol-induced steatosis 923 leads to increased immune tolerance after liver transplantation (13), chronic hepatitis virus infection (14), and hepatocellular carcinoma (15). A recent study indicated a significant decrease of peripheral blood Tregs in patients with alcoholic hepatitis, implying the significance of Tregs in the pathogenesis of ALD (16).…”

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confidence: 99%

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Wang¹,

Wu²,

Wang³

et al. 2019

Journal of Lipid Research

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Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Regulatory T cells (Tregs) are an immunosuppressive cell subset that plays an important role in a variety of liver diseases; however, data about pathological involvement of Tregs in liver steatosis of alcoholic liver disease (ALD) is insufficient. In mouse models of ALD, we found that increased lipid accumulation by chronic alcohol intake was accompanied by oxidative stress, inflammatory accumulation, and Treg decline in the liver. Adoptive transfer of Tregs relieved lipid metabolic disorder, oxidative stress, inflammation, and, consequently, ameliorated the alcoholic fatty liver. Macrophages are a dominant source of inflammation in ALD. Aberrant macrophage activation and cytokine production were activated during chronic alcohol consumption, but were significantly inhibited after Treg transfer. In vitro, macrophages were co-activated by alcohol and lipopolysaccharide to mimic a condition for alcoholic liver microenvironment. Tregs suppressed monocyte chemoattractant protein-1 and TNF-α production from these macrophages. However, such effects of Tregs were remarkably neutralized when interleukin (IL)-10 was blocked. Altogether, our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.

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confidence: 99%

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Wang¹,

Wu²,

Wang³

et al. 2019

Journal of Lipid Research

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“…Overall, the Treg-resistant phenotype of Tcon cells appears to be relatively stable, able to persist in the absence of pro-inflammatory cytokines or other resistance-inducing factors. Future studies will need to assess the ability of Tcon cells to maintain Treg resistance, especially in light of efforts to use adoptive Treg therapy for treatment of autoimmune diseases ( 186 ). Infusion of Tregs into patients with Tcon cells resistant to suppression might prove to be ineffective, and should be examined further.…”

Section: Remaining Questionsmentioning

confidence: 99%

Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression

Mercadante

Lorenz

2016

Front. Immunol.

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Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function. However, evidence has accumulated in recent years to suggest that Tcon cell resistance to Treg-mediated suppression centrally contributes to the pathogenesis of autoimmune disease. Tipping the balance too far in the other direction, cancerous tumors utilize Tregs to establish an overly suppressive microenvironment, preventing antitumor Tcon cell responses. Given the wide-ranging clinical importance of the Tcon/Treg interaction, this review aims to provide a better understanding of what determines whether a Tcon cell is susceptible to Treg-mediated suppression and how perturbations to this finely tuned balance play a role in pathological conditions. Here, we focus in detail on the complex array of factors that confer Tcon cells with resistance to Treg suppression, which we have divided into two categories: (1) extracellular factor-mediated signaling and (2) intracellular signaling molecules. Further, we explore the therapeutic implications of manipulating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is proposed to be the convergence point of signaling pathways that mediate Tcon resistance to suppression. Finally, we address important unresolved questions on the timing and location of acquisition of resistance, and the stability of the “Treg-resistant” phenotype.

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“…Regulatory T cells (Treg) play a central role in immune homeostasis and prevention of autoimmune diseases [1][2][3]. In a variety of transplantation and autoimmune mouse models, injection of Treg prevented immune pathology [4][5][6][7]. Promising clinical effects of Treg therapy with expanded Treg in the treatment of patients with graft versus host disease (GvHD) have been demonstrated [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Treg-based therapy could reduce toxicity and side effect in comparison with immunosuppressive drugs. The ultimate goal of Treg therapy would be induction of tolerance without immune suppression-related development of malignancies and infections [4,5,20]. Despite the current successes of Treg-based therapy, it is still not precisely known how and where immune regulation by injected Treg take place and in which anatomical side the inflammatory processes are controlled.…”

Section: Introductionmentioning

confidence: 99%

Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+ Cells in a Humanized Mouse Model of Skin Inflammation

Landman

Oliveira

Peppelman

et al. 2020

Journal of Immunology Research

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Background. Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods. SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20‐40×106 allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results. We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion. Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.

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Adoptive T Regulatory Cell Therapy for Tolerance Induction

Cited by 10 publications

References 116 publications

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression

Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+ Cells in a Humanized Mouse Model of Skin Inflammation

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