Harnessing regulatory T cells for transplant tolerance in the clinic through mTOR inhibition

2011 ◽  
Vol 16 (6) ◽  
pp. 606-613 ◽  
Author(s):  
Julien Zuber ◽  
Olivier Hermine ◽  
Lucienne Chatenoud ◽  
Christophe Legendre
2021 ◽  
Author(s):  
Yannick D. Muller ◽  
Leonardo M.R. Ferreira ◽  
Emilie Ronin ◽  
Patrick Ho ◽  
Vinh Nguyen ◽  
...  

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-zeta signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.


2018 ◽  
Vol 4 (4) ◽  
pp. 205-213 ◽  
Author(s):  
Eman Shaban ◽  
George Bayliss ◽  
Deepak K. Malhotra ◽  
Douglas Shemin ◽  
Li Juan Wang ◽  
...  

2014 ◽  
Vol 162 (1) ◽  
pp. 74-86 ◽  
Author(s):  
Juan Shan ◽  
Li Feng ◽  
Youping Li ◽  
Guixiang Sun ◽  
Xuelu Chen ◽  
...  

2015 ◽  
Vol 6 ◽  
Author(s):  
Paulina Ruiz ◽  
Paula Maldonado ◽  
Yessia Hidalgo ◽  
Daniela Sauma ◽  
Mario Rosemblatt ◽  
...  

2011 ◽  
pp. 1
Author(s):  
James I. Kim ◽  
Matthew R. OʼConnor ◽  
Patrick E. Duff ◽  
Gaoping Zhao ◽  
Kang Mi Lee ◽  
...  

JCI Insight ◽  
2017 ◽  
Vol 2 (3) ◽  
Author(s):  
Elodie Picarda ◽  
Séverine Bézie ◽  
Laetitia Boucault ◽  
Elodie Autrusseau ◽  
Stéphanie Kilens ◽  
...  

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Abbas Shahi ◽  
Saeedeh Salehi ◽  
Shima Afzali ◽  
Ladan Gol Mohammad Pour Afrakoti ◽  
Marzie Esmaeili ◽  
...  

Background. Regulatory T cells (Tregs) and recent thymic emigrants (RTEs) have an essential role in the regulation of allogeneic immune responses. However, their mechanisms of action in chronic antibody-mediated rejection (cAMR) are still unclear. In this study, we aimed to compare Treg and RTE levels between stable graft function (SGF) patients and cAMR subjects after kidney transplantation. Method. Mononuclear cells (MNs) were separated from peripheral blood, and flow cytometry analysis was performed for detection of CD4+ and CD25high as Treg markers and CD4+, CD31+, and CD45RA+ as RTE immunophenotyping markers. Result. The level of peripheral Treg cells was significantly lower in cAMR subjects in comparison to stable graft function patients. Moreover, SGF patients who had received cyclosporine A had a higher level of Treg in comparison to the tacrolimus recipients. Nevertheless, the RTE level between SGF and cAMR patients did not show any significant differences. Conclusion. It seems that Treg cells are significantly associated with transplant outcomes in cAMR patients, and prescribed immunosuppressive drugs can influence the frequency of this crucial subset of T cells. Although these drugs are beneficial and inevitable for allograft maintenance, more investigations are needed to elucidate their complete effects on different immune cell subsets which some of them like Tregs are in favor of transplant tolerance. Besides, the thymic output is seemingly not a beneficial biomarker for predicting cAMR; however, more in vivo and in vitro studies are needed for revealing the precise role of Tregs and RTEs in the transplantation context.


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