Regulatory T cells: tolerance induction in solid organ transplantation

Vaikunthanathan, Trishan; Safinia, Niloufar; Boardman, Dominic A.; Lechler, Robert I.; Lombardi, Giovanna

doi:10.1111/cei.12978

Cited by 60 publications

(58 citation statements)

References 137 publications

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“…Preparation of Tregs by ex vivo expansion is being investigated but this approach is expensive and its effectiveness still uncertain. In light of these problems, the alternative approach of boosting Treg cell numbers in situ is clearly attractive (9).…”

mentioning

confidence: 99%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Injection of Interleukin-2 (IL-2) complexed with a particular anti–IL-2 monoclonal antibody (mab) JES6-1 has been shown to selectively expand CD4+Foxp3+ T regulatory T cells (Tregs) in vivo. Although the potency of this approach with regard to transplantation has already been proven in an islet transplantation model, skin graft survival could not be prolonged. Since the latter is relevant to human allograft survival, we sought to improve the efficiency of IL-2 complex (cplx) treatment for skin allograft survival in a stringent murine skin graft model. Here, we show that combining low doses of IL-2 cplxs with rapamycin and blockade of the inflammatory cytokine IL-6 leads to long-term (>75 d) survival of major histocompatibility complex-different skin allografts without the need for immunosuppression. Allograft survival was critically dependent on CD25+FoxP3+ Tregs and was not accompanied by impaired responsiveness toward donor alloantigens in vitro after IL-2 cplx treatment was stopped. Furthermore, second donor-type skin grafts were rejected and provoked rejection of the primary graft, suggesting that operational tolerance is not systemic but restricted to the graft. These findings plus the lack of donor-specific antibody formation imply that prolonged graft survival was largely a reflection of immunological ignorance. The results may represent a potentially clinically translatable strategy for the development of protocols for tolerance induction.

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mentioning

confidence: 99%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…A combination of CD4 + CD25 + and CD127 low expression is commonly used for the characterization of Tregs, regularly together with forkead box P3 (Foxp3). 7 In several studies, Tregs have been implicated as being part of the process in T1D. 8,9 However, characterization and determination of the role of memory Tregs in T1D still need investigation.…”

Section: Introductionmentioning

confidence: 99%

Altered expression of CD39 on memory regulatory T cells in type 1 diabetes patients

Jin

Zhang

Gong

et al. 2018

Journal of Diabetes

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Background Type 1 diabetes (T1D) is an autoimmune disease resulting from an attack by autoreactive T lymphocytes against pancreatic islet β‐ cells. In recent studies, regulatory T cells (Tregs) have been implicated in the process of T1D. Furthermore, cluster of differentiation 39 (CD39), which is involved in the suppression of inflammation, has been shown to be expressed on Tregs. However, the pathological importance of CD39 to the memory Treg population remains unclear. Methods This study investigated Treg subsets, focusing on resting, effector, and memory Tregs, and determined CD39 expression on Tregs. In addition, changes in Treg subsets and Treg‐associated cytokine secretion after CD3/CD28 stimulation of peripheral blood mononuclear cells were evaluated in diabetic patients and healthy controls. The suppressive function of Tregs was measured using the mixed lymphocyte reaction (MLR) test. Results There was a higher percentage of memory Tregs in T1D patients than healthy controls. However, Tregs in T1D patients showed impaired suppression, with low forkhead box P3 (Foxp3) expression and low serum interleukin (IL)‐10 levels. Furthermore, CD39 expression on Tregs, and on memory Tregs in particular, was lower in T1D patients than healthy controls. After stimulation, the percentage of resting Tregs was decreased and that of effector/memory Tregs was increased in both healthy controls and T1D patients, but CD39 expression on effector/memory Tregs was still lower and there was no increase in IL‐10 secretion in T1D patients. Conclusions The defective suppressive function of Tregs in T1D patients is due to lower expression of CD39 on memory Tregs.

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“…To date, studies of Tregs in transplantation have focused on non-antigen-specific thymusderived naïve CD4+CD25+FOXP3+ T cells, which are fresh or activated by IL-2 only or IL-2 plus anti-CD3 antibody [23,24]. ese cells express the transcription factor FOXP3, which inhibits IL-2 transcription, and promote the induction of transplant tolerance [25,26], typically via cell contact-dependent and cell contact-independent mechanisms, ranging from cytokine release, receptor endocytosis, and purinergic signaling to cell cytotoxic mechanisms [27][28][29].…”

Section: Experimental Heart Transplantationmentioning

confidence: 99%

The Role of IL-33 in Experimental Heart Transplantation

Chen

Xie

Wei

et al. 2020

Cardiology Research and Practice

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Interleukin-33 (IL-33) is a member of the IL-1 family of proteins that are produced by a variety of cell types in multiple tissues. Under conditions of cell injury or death, IL-33 is passively released from the nucleus and acts as an "alarmin" upon binding to its specific receptor ST2, which leads to proinflammatory or anti-inflammatory effects depending on the pathological environment. To date, numerous studies have investigated the roles of IL-33 in human and murine models of diseases of the nervous system, digestive system, pulmonary system, as well as other organs and systems, including solid organ transplantation. With graft rejection and ischemia-reperfusion injury being the most common causes of grafted organ failure or dysfunction, researchers have begun to investigate the role of IL-33 in the immune-related mechanisms of graft tolerance and rejection using heart transplantation models. In the present review, we summarize the identified roles of IL-33 as well as the corresponding mechanisms by which IL-33 acts within the progression of graft rejection after heart transplantation in animal models.

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Regulatory T cells: tolerance induction in solid organ transplantation

Cited by 60 publications

References 137 publications

Treg-mediated prolonged survival of skin allografts without immunosuppression

Treg-mediated prolonged survival of skin allografts without immunosuppression

Altered expression of CD39 on memory regulatory T cells in type 1 diabetes patients

The Role of IL-33 in Experimental Heart Transplantation

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