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• W2580452210 abstract "In response to the article by Boardman et al (page 931), the authors provide a brief update on chimeric antigen receptor technology, particularly regarding regulatory T cells in the context of transplantation. In response to the article by Boardman et al (page 931), the authors provide a brief update on chimeric antigen receptor technology, particularly regarding regulatory T cells in the context of transplantation. Long-term graft acceptance of a transplanted organ is possible thanks to daily intake of immunosuppressive drugs. Tremendous efforts and progress have been made to improve drug efficiency, but current immunosuppressive treatments are still unable to prevent rejection in the long term and are associated with a significant risk of tumor development. Novel next-generation strategies, avoiding panimmunosuppression, are urgently required to target alloreactive T cells and graft rejection. Regulatory T cells (Tregs), the role of which has been demonstrated mainly in rodent models, are currently under study in several clinical trials to treat various diseases including kidney and liver transplant rejection. Since the first report of the regulatory effect of T cells in the 1970s (1Gershon RK Kondo K Cell interactions in the induction of tolerance: The role of thymic lymphocytes.Immunology. 1970; 18: 723-737PubMed Google Scholar), the identification of a population of CD4+CD25+ T cells with regulatory properties in vivo was reported by Sakaguchi et al only in 1995 (2Sakaguchi S Sakaguchi N Asano M Itoh M Toda M Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J. Immunol. 1995; 155: 1151-1164Crossref PubMed Google Scholar). Numerous papers were then published revealing their phenotype, role, and effect in vitro and in vivo in different pathologies. The possibility of adoptive transfer to allow “Treg therapy” thus emerged as a treatment that was potentially transferable to the clinic. The benefit of such therapy in humans relies on the possibility of isolation and expansion of Tregs (despite the absence of specific cell-surface markers) ex vivo and their reinjection in vivo under good manufacturing practice (GMP) conditions. This explains why such a process is only now envisaged in the clinical setting. Moreover, its success and potential depends on the possibility of exploiting antigen-specific Tregs. The first demonstration of the use of antigen-specific T cells with regulatory properties was reported in the 1980s by Eshhar’s group (3Gross G Waks T Eshhar Z Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.Proc Natl Acad Sci USA. 1989; 86: 10024-10028Crossref PubMed Scopus (987) Google Scholar). Since then, several generations of allospecific Tregs have been tested and have clearly shown superior immunosuppression compared with polyclonal Tregs (4Tang Q Henriksen KJ Bi M et al.In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes.J Exp Med. 2004; 199: 1455-1465Crossref PubMed Scopus (984) Google Scholar). Different approaches have been taken to generate Tregs with defined antigen specificity. In this paper, the authors investigate whether allospecificity may be conferred onto Tregs using the synthetic fusion protein chimeric antigen receptor (CAR) technology, which is able to redirect T cell antigen specificity by targeting donor MHC molecules with the aim of promoting organ transplant tolerance (5Boardman DA Philippeos C Fruhwirth GO et al.Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection.Am J Transplant. 2016; (doi: 10.1111/ajt.14185 (Epub ahead of print).)Google Scholar). CAR technology has been exploited mainly in the treatment of different human cancers and is now emerging as a potential treatment for autoimmune diseases but, to date, has not been tested in transplantation. The authors tested, in vitro and in vivo in a human skin xenograft transplant model, two novel HLA-A2–specific CARs, one including a CD28-CD3ζ signaling domain and one lacking an intracellular signaling domain, to redirect human polyclonal CD4+CD25+CD127loFOXP3+ Tregs toward donor-MHC class I molecules. They first report that CD4+CD25+CD127loFOXP3+ Tregs expressing CAR following lentiviral transduction are specific for HLA-A2 antigens and may be expanded ex vivo. Second, in vitro CD4+CD25+CD127loFOXP3+ Tregs maintain their phenotype and function, are even more suppressive than polyclonal Tregs, lack cytotoxic activity, and have a higher capacity for endothelial cell transmigration, thereby supporting their potential application in clinical practice. In vivo, the authors report that CAR Tregs are preferentially recovered in the graft, suggesting their capacity for a local and targeted suppressive effect (and demonstrated by the particularly relevant readout of CD31+ blood vessel integrity). This novel demonstration of CAR Treg application offers important perspectives for the future, not only in cancer, graft-versus-host disease, and autoimmune diseases but also in avoiding organ transplant rejection and even in promoting specific tolerance. It is particularly intriguing that underlying mechanisms of the efficiency of donor-specific CAR Tregs include their ability to migrate to and to remain in the graft at the site of specific alloantigen expression, although the mediators of homing and retention are as yet unknown. Successful translation of this technique to routine clinical use in transplantation will be a long process, but the development of GMP-grade Tregs per se is now a reality. Efforts to improve the quality of the injected cells and to generate more efficient next-generation CAR Tregs are required. New paths of investigation can be probed based on the implication of transendothelial migration, homing, and graft retention shown in this paper and will depend on further characterization of the intrinsic nature of T cell subsets and the complexity of their differentiation, particularly in a defined situation (e.g. allogenicity with regard to organ transplantation) to pursue their use in effective personalized therapy. This new method of immunotherapy also offers multiple possibilities including genetic, epigenetic, and metabolic modifications of these “genetically engineered CAR-T cells” to increase their safety, potency, and applicability. Such developments will pave the way for precision medicine for a maximum number of patients. We would like to acknowledge funding from the European Commission’s Seventh Framework Program FP7-HEALTH-2012 under grant agreement n°305147 BIO-DrIM and n°602470 VISICORT. French research network in transplantation, the DHU Oncogreffe and the LabEX IGO program supported by the National Research Agency via the investment of the future program ANR-11-LABX-0016-01 and the LABEX TRANSPLANTEX [ANR-11-LABX-0070_TRANSPLANTEX]. This research was also promoted by INSERM and IHU-CESTI institutes who provided financial support as well as CENTAURE national RTRS. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation." @default.
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• W2580452210 title "Synthetic Fusion Protein CAR Technology to Redirect T Cell Antigen Specificity to Promote Organ Transplant Tolerance" @default.
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• W2580452210 doi "https://doi.org/10.1111/ajt.14211" @default.
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