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There is now compelling evidence for subpopulations of CD4+ T cells whose role is to prevent immune pathology in both autoimmunity and transplantation. We have cloned CD4+ T cells against a male transplantation Ag that, unlike Th1 or Th2 clones, suppresses the rejection of male skin grafts and are therefore considered examples of regulatory T cells...
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... then proceeded to compare the expression of the remaining gene candidates, by TaqMan quantitative RT-PCR, on resting and activated T cell clones and fractionated subpopulations of normal spleen CD4 T cells (Fig. 4). Of particular interest was the finding that ppENK was not expressed in resting Th1 or CD4 CD25 cells, and even after activation it remained low or undetectable, respectively, while it was highly expressed and further up-regu- lated after activation in Treg, Tskin, and normal spleen CD4 CD25 T cells. GM2a was not expressed on Th1 or ...
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... En effet, alors même qu'ils possèdent une activité proinflammatoire, il a été montré de manière inattendu qu'ils jouaient un rôle indispensable dans la tolérance allogreffe (Lu (Lu, Lind et al. 2006)LF et al., 2006. De manière intéressante, l'analyse de l'expression des gènes dans les allogreffes tolérantes a révélé une augmentation des transcrits pouvant être associée aux mastocytes (Zelenika D. et al. 2002). Mais ce n'est qu'après les travaux de recherche de Noëlle et al en 2006, dans un modèle de tolérance que les mastocytes ont été clairement impliqués dans l'induction de la tolérance de la greffe de peau. ...
... Cette déficience conduit à une maladie auto-immune multi-organe qui inclut des immunopathologies cutanées, récapitulant lesimmunopathologies sévères observées chez les souris Scurfy (souris possédant une mutation sur le gène codant pour FOXP3 conduisant à une absence de Tregs dans le système immunitaire) et chez des patients atteints de syndrome d'immunodépression humaine, de polyendocrinopathie et d'entéropathie, liés au chromosome X (IPEX) (McGinness, Bivens et al. 2006). Nonseulement la protéine FOXP3 contrôle l'expression de nombreux marqueurs identifiés préalablement comme le CD45RB low (Hara, Kingsley et al. 2001), le CTLA-4 (« cytotoxic Tlymphocyte antigen 4 »; CD152)(Kingsley, Karim et al. 2002), le CD62L (L-sélectine)(Herbelin, Gombert et al. 1998), le GITR (« glucocorticoid-induced tumor-necrosis factor receptor »)(Zelenika, Adams et al. 2002), le CD122 (chez les cellules humaines seulement)(Levings, Sangregorio et al. 2001), le CD103(Zelenika, Adams et al. 2002), le CD25 (sous-unité α du récepteur de l'IL-2(Sakaguchi, Sakaguchi et al. 1995);(Thornton and Shevach 1998) mais son induction sur les cellules T CD4 naives permet l'obtention de cellules immunosuppressives in vitro et in vivo(Hori, Nomura et al. 2003). En outre, la présence de cellules T CD4 + CD25 + dans le thymus et en périphérie associée à un niveau d'expression faible du CD127 ( chaine α du récepteur à l'IL-7) chez les souris exprimant les molécules de CMH-II exclusivement dans le cortex, ((Bensinger, Bandeira et al. 2001)indique une sélection des Tregs par le CMHII. ...
... Cette déficience conduit à une maladie auto-immune multi-organe qui inclut des immunopathologies cutanées, récapitulant lesimmunopathologies sévères observées chez les souris Scurfy (souris possédant une mutation sur le gène codant pour FOXP3 conduisant à une absence de Tregs dans le système immunitaire) et chez des patients atteints de syndrome d'immunodépression humaine, de polyendocrinopathie et d'entéropathie, liés au chromosome X (IPEX) (McGinness, Bivens et al. 2006). Nonseulement la protéine FOXP3 contrôle l'expression de nombreux marqueurs identifiés préalablement comme le CD45RB low (Hara, Kingsley et al. 2001), le CTLA-4 (« cytotoxic Tlymphocyte antigen 4 »; CD152)(Kingsley, Karim et al. 2002), le CD62L (L-sélectine)(Herbelin, Gombert et al. 1998), le GITR (« glucocorticoid-induced tumor-necrosis factor receptor »)(Zelenika, Adams et al. 2002), le CD122 (chez les cellules humaines seulement)(Levings, Sangregorio et al. 2001), le CD103(Zelenika, Adams et al. 2002), le CD25 (sous-unité α du récepteur de l'IL-2(Sakaguchi, Sakaguchi et al. 1995);(Thornton and Shevach 1998) mais son induction sur les cellules T CD4 naives permet l'obtention de cellules immunosuppressives in vitro et in vivo(Hori, Nomura et al. 2003). En outre, la présence de cellules T CD4 + CD25 + dans le thymus et en périphérie associée à un niveau d'expression faible du CD127 ( chaine α du récepteur à l'IL-7) chez les souris exprimant les molécules de CMH-II exclusivement dans le cortex, ((Bensinger, Bandeira et al. 2001)indique une sélection des Tregs par le CMHII. ...
L'allogreffe de peau est réalisée suite à des blessures, brûlures ou autres maladies de la peau afin de palier à la perte de protection de la peau. Induire une meilleure tolérance du greffon en évitant ou diminuant le dosage des traitements immunosuppresseurs et leurs effets secondaires est un vrai défi. Les mastocytes, cellules du système immunitaire cutané, forment un véritable réseau dans la peau participant aux mécanismes de défense de l’hôte. Décrit pour leurs effets bénéfiques en condition de tolérance de greffe par les lymphocytes T régulateur, nous nous sommes intéressés au contrôle du rejet de greffe par les mastocytes. Grâce au nouveau modèle murin (RMB) développé au laboratoire permettant leur visualisation par fluorescence et leur déplétion par injection de toxine diphtérique, nous avons utilisé un modèle de greffe de peaux d’oreille de souris mâles sur des souris femelles. Nos résultats montrent une accélération du rejet du greffon en présence de mastocytes (t1/2 3 versus 6 jours). Nous avons observé un recrutement important de cellules inflammatoires à la fois au niveau de la greffe et dans les ganglions drainants à 2 et 6 jours par rapport au greffe femelle-femelle dont la réponse inflammatoire est associée une réparation tissulaire après la greffe. Nous avons remarqué une augmentation de l'expression de cytokines inflammatoires telles que KC, MIP-2 et TNF justifiant l'infiltration précoce des neutrophiles pour faciliter le rejet du greffon. En outre, l’administration de la cromolyne, un stabilisateur des MCs et, dans une moindre mesure, de la kétotifène, un antagoniste des récepteurs histaminiques de type I, et l'absence de la chymase MCPT4 retardait également le rejet du greffon montrant que les MC sécrète de l'histamine et la MCPT4 au cours du rejet. Nous avons confirmé l'impact des neutrophiles sur ce processus de rejet en montrant que leur déplétion avec un anticorps spécifique retarde le rejet de la peau comme en absence de MCs. L’ensemble de ces données indique que les mastocytes après la dégranulation favorisent le recrutement de cellules inflammatoires, telles que les neutrophiles, qui contribuent à l'accélération du rejet de la greffe de peau de l'oreille.
... The need for reductionist systems to study therapeutic transplantation tolerance led us to use TCR transgenic mice whose only adaptive lymphocytes were CD4 T cells carrying a TCR directed to a single minor transplantation antigen (the male antigen Dby) (33)(34)(35). Female mice carried no T cells expressing Foxp3, as they could not generate the natural Tregs that conventional mice produce in their thymus. Females could be tolerized to male skin grafts by a short pulse of anti-CD4 treatment (18). ...
Induction of Immunological Tolerance as a Therapeutic Procedure, Page 1 of 2
Abstract
A major goal of immunosuppressive therapies is to harness immune tolerance mechanisms so as to minimize unwanted side effects associated with protracted immunosuppressive therapy. Antibody blockade of lymphocyte coreceptor and costimulatory pathways in mice has demonstrated the principle that both naive and primed immune systems can be reprogrammed toward immunological tolerance. Such tolerance can involve the amplification of activity of regulatory T cells, and is maintained through continuous recruitment of such cells through processes of infectious tolerance. We propose that regulatory T cells create around them microenvironments that are anti-inflammatory and endowed with enhanced protection against destructive damage. This acquired immune privilege involves the decommissioning of cells of the innate as well as adaptive immune systems. Evidence is presented that nutrient sensing by immune cells acting through the mammalian target of rapamycin (mTOR) pathway provides one route by which the immune system can be directed toward noninflammatory and regulatory behavior at the expense of destructive functions. Therapeutic control of immune cells so as to harness metabolic routes favoring dominant regulatory mechanisms has offered a new direction for immunosuppressive therapy, whereby short-term treatment may be sufficient for long-term benefit or even cure.
... Constitutive expression of GITR in murine tTregs was first described by McHugh et al. [35] and Shimizu et al. [26] and was confirmed by Zelenika et al. [133]. Cells with suppressive activity express high levels of GITR in FoxP3 transgenic mice [134]. ...
Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-), the presence of GITR+ cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs.
... The evidence showing that GITR plays a crucial role in the maturation of tTregs, effector/pTreg switch and expansion of both tTregs and pTregs suggests that GITR may be useful for the identification of Tregs. Strong expression of GITR in murine Tregs was first described by McHugh et al. [60] and Shimizu et al. [61] and confirmed by Zelenika et al. [62], and its tissue distribution and function has been reviewed by Nocentini and Riccardi [63]. ...
Autoimmune diseases decrease life expectancy and quality of life for millions of women and men. Although treatments can slow disease progression and improve quality of life, all currently available drugs have adverse effects and none of them are curative; therefore, requiring patients to take immunosuppressive drugs for the remainder of their lives.A curative therapy that is safe and effective is urgently needed. We believe that therapies promoting the in vivo expansion of regulatory T cells (Tregs) or injection of in vitro expanded autologous/heterologous Tregs (cellular therapy) can alter the natural history of autoimmune diseases.In this review, we present data from murine and human studies suggesting that 1) glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) plays a crucial role in thymic Treg (tTreg) differentiation and expansion; 2) GITR plays a crucial role in peripheral Treg (pTreg) expansion; 3) in patients with Sjögren syndrome and systemic lupus erythematosus, CD4+GITR+ pTregs are expanded in patients with milder forms of the disease; and 4) GITR is superior to other cell surface markers to differentiate Tregs from other CD4+ T cells.In this context, we consider two potential new approaches for treating autoimmune diseases consisting of the in vivo expansion of GITR+ Tregs by GITR-triggering drugs and in vitro expansion of autologous or heterologous GITR+ Tregs to be infused in patients. Advantages of such an approach, technical problems, and safety issues are discussed.
... TGF-b is particularly produced by non-foxp3-expressing Th3 cells implicated in some models of oral tolerance (Fukaura et al. 1996), while IL-10 secretion is a characteristic feature of the foxp3 negative Tr1 cell subset (Groux et al. 1997). And, like Treg, they can constitutively express CTLA4 (Zelenika et al. 2002;Mellor et al. 2004). Adoptive transfer of purified or cloned antigenspecific Tr1 cells can block the induction of inflammatory bowel disease in mice and seem to be as effective as foxp3 þ Treg in suppressing allogeneic skin graft rejection (Zelenika et al. 2002). ...
... And, like Treg, they can constitutively express CTLA4 (Zelenika et al. 2002;Mellor et al. 2004). Adoptive transfer of purified or cloned antigenspecific Tr1 cells can block the induction of inflammatory bowel disease in mice and seem to be as effective as foxp3 þ Treg in suppressing allogeneic skin graft rejection (Zelenika et al. 2002). IL-10-secreting Tr1 cells also seem to play an important role in regulating allergic responses in humans (Akdis et al. 2004;Mobs et al. 2010)-with some of the best evidence coming from the studies of seasonal and reciprocal changes in cytokine-secreting T-cell subsets and in response to immunotherapy (McHugh et al. 1996;Fellrath et al. 2003). ...
Transplantation tolerance is a continuing therapeutic goal, and it is now clear that a subpopulation of T cells with regulatory activity (Treg) that express the transcription factor foxp3 are crucial to this aspiration. Although reprogramming of the immune system to donor-specific transplantation tolerance can be readily achieved in adult mouse models, it has yet to be successfully translated in human clinical practice. This requires that we understand the fundamental mechanisms by which donor antigen-specific Treg are induced and function to maintain tolerance, so that we can target therapies to enhance rather than impede these regulatory processes. Our current understanding is that Treg act via numerous molecular mechanisms, and critical underlying components such as mTOR inhibition, are only now emerging.
... In peripheral tissues subpopulations of opioid peptidecontaining cells include granulocytes, monocytes/macrophages and lymphocytes (reviewed in [73]). Most notably, regulatory T cells (Tregs, a population suppressing inflammatory responses) were shown to express the PENK gene [82,83]. ...
Opioids are the gold standard for pain treatment but systemic opioid use is accompanied by central and intestinal side effects. As opioid receptors are expressed on peripheral sensory nerve endings, cutaneous and immune cells, local opioid application is being used for pain reduction in patients with inflammatory lesions such as burns, skin grafts, arthritis, acute or chronic wounds. In addition, peripherally active opioids have anti-inflammatory effects and can modulate wound healing. This review will cover anatomical, physiological and pathophysiological characteristics of opioid receptors and their ligands in peripheral tissues. We will then focus on mechanisms and the functional role of peripheral opioids in inflammation and wounds in experimental and clinical studies. Controversial results, methodological issues, implications for pharmacology, and therapeutic prospects for inflammatory diseases and wound healing will be discussed.
... In peripheral tissues subpopulations of opioid peptidecontaining cells include granulocytes, monocytes/macrophages and lymphocytes (Przewłocki et al., 1992;Mousa et al., 2001Mousa et al., , 2007bRittner et al., 2001Rittner et al., , 2007aLabuz et al., 2006Labuz et al., , 2010Verma-Gandhu et al., 2006;Zöllner et al., 2008). Most notably, regulatory T cells (a population suppressing inflammatory responses) were shown to express the PENK gene (McHugh et al., 2002;Zelenika et al., 2002). ...
The concept that the immune system can communicate with peripheral sensory neurons to modulate pain is based mostly on documented interactions between opioid ligands and receptors. Such findings may have broad implications for the development of safer pain medication. Innovative strategies take into account that analgesics should be particularly active in pathological states rather than producing a general suppression of the central nervous system, as with conventional morphine- or cannabinoid-like drugs. Inflammation of peripheral tissue leads to increased functionality of opioid receptors on peripheral sensory neurons and to local production of endogenous opioid peptides. In addition, endocannabinoids were detected in leukocytes, but their role in pain modulation has yet to be addressed. Future aims include the development of peripherally restricted opioid agonists, selective targeting of opioid-containing immune cells to sites of painful injury, and the augmentation of peripheral ligand and receptor synthesis (e.g., by gene therapy). Similar approaches may be pursued for cannabinoids. The ultimate goal is to avoid detrimental side effects of currently available analgesics such as respiratory depression, cognitive impairment, addiction, gastrointestinal bleeding, and thromboembolic complications.
... The IL-2 and IL-4 anti-apoptotic effect might concern different subpopulations of the CD4 + CD25 ) T cells. It was demonstrated that IL-2 is able to selectively protect Th1 lymphocytes from glucocorticoid-induced apoptosis, whereas IL-4 was required for Th2 type cells (23,24). Even though CD4 + CD25 High T cells have been reported to share characteristics with Th2 cells (25), IL-2 was shown to protect CD4 + CD25 + T cells from Dex-induced apoptosis exclusively (26). ...
Heligmosomoides bakeri infection in mice is associated with a dominant CD4(+) T-cell response and with the activity of natural Treg cells with CD4(+) CD25(+) phenotype. The polarization of Th2 T-cell phenotype and the increase in the CD4(+) CD25(+) T cell population are regulated by glucocorticoids that induce apoptosis in CD4(+) CD25(-) T cells and inhibit apoptosis in CD4(+) CD25(+) T cells. However, exposure of mice to H. bakeri antigen induces a high glucocorticoid concentration in serum and a reduction in the number of CD4-positive; CD4(+) CD25(-) and CD4(+) CD25(+) apoptotic T cells in mesenteric lymph node cells. In this study to evaluate the in vitro effect of the anti-apoptotic property of H. bakeri antigen on T cells, apoptosis of these cells was induced by glucocorticoids-dexamethasone (Dex). Excretory-secretory (ES) antigen of the nematode prevented Dex-induced apoptosis in CD4-positive T cells with CD4(+) CD25(-) and CD4(+) CD25(High) phenotype by Bcl-2 protein expression. Contrary to the effect on CD4-positive T cells, survival of CD8(+) T cells was not connected with expression of Bcl-2 protein. This suggest that H. bakeri antigen modulates CD4-positive T cell sensitivity to glucocorticoid-induced apoptosis by induction of Bcl-2 protein.
... To date, the best surface marker profile for murine Treg with alloregulatory capacity is CD3 + CD4 + CD25 + GITR + [36] [37]. There is evidence that GITR is overexpressed in tolerant mouse skin grafts when compared to rejected grafts [38]. It is important to emphasize that GITR or other surface markers do not themselves confer regulatory capacity. ...
Every year individuals receive hematopoietic stem cell transplantation (HSCT) to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT) and regulatory T cells (Treg), and their current and potential roles in tolerance induction after allogeneic HSCT.
... Matsui et al. [31] identified two genes (H2-Ea and Frzb) that were highly expressed in long-term surviving heart allografts. Moreover, another group has recently reported an interesting upregulation of specific set of genes (TGF- b2, ppENK, GM2a, GITR, and IL-1R2) in regulatory T cells (Tregs) associated with tolerance of skin allografts [32, 33]. Some reports have assessed the gene expression profile (GEP) in different settings during renal transplantation. ...
Aim of Review. Huge effort is being made among the transplant community investigating novel biomarkers that enable transplant clinicians to identify patients at risk for allograft rejection or those who will develop tolerance so that immunosuppression could be safely minimized or even ideally withdrawn. Despite the important advances achieved in the identification of several potential biomarkers of tolerance, rejection, or both, validation and demonstration of their clinical utility still needs to be tested, which will need international cooperative networks. It is important to note that the reproducibility of differently expressed genes might be affected by many factors such as gene ranking and selection methods, inherent differences between types, and the choice of thresholds. However, because microarray analyses are expensive and time consuming and their statistical evaluation is often very difficult, gene expression analysis using the RTPCR method is nowadays recommended. Conclusions. In the field of organ transplantation, gene-expression-based decision might help in improving patient and graft outcome and there are a multitude of studies showing that gene-expression profiling is feasible.
