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Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation.

ABSTRACT: Regulatory T cells (Tregs) modulate the function of a variety of immune cells and are critical for maintaining self-tolerance and preventing the development of autoimmune disease. Due to their ability to suppress effector T cells, Tregs have been increasingly explored for clinical use to suppress alloresponses. While this approach has been promising in preclinical models and early clinical trials, widespread clinical use of Tregs has been limited by the low number of these cells in the periphery and the unknown frequency of allo-responsive Tregs. In this issue of the JCI, MacDonald and colleagues transduced human Tregs with a chimeric antigen receptor (CAR) that targets the HLA class I molecule A2. These CAR-expressing T cells were readily activated via CAR stimulation and exerted potent immunosuppressive effects when stimulated in vitro. In a murine model of hematopoietic stem cell transplantation, CAR-modified Tregs were more effective in preventing the development of graft-versus-host disease compared with polyclonal Tregs. The results of this study lay the groundwork for the further evaluation of CAR-expressing Tregs in the prevention or treatment of transplant complications.

SUBMITTER: Edinger M

PROVIDER: S-EPMC4811145 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation.

Edinger Matthias M

The Journal of clinical investigation 20160321 4

Regulatory T cells (Tregs) modulate the function of a variety of immune cells and are critical for maintaining self-tolerance and preventing the development of autoimmune disease. Due to their ability to suppress effector T cells, Tregs have been increasingly explored for clinical use to suppress alloresponses. While this approach has been promising in preclinical models and early clinical trials, widespread clinical use of Tregs has been limited by the low number of these cells in the periphery ...[more]

PMID: 26999608

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Project description:Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

Dataset Information

Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation.

Publications

Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation.

Similar Datasets

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