Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys

Ma, Anlun; Qi, Shijie; Song, Lijun; Hu, Yanxin; Dun, Hao; Massicotte, Eric M.; Dupuis, Martine; Daloze, Pierre; Chen, Huifang

doi:10.1016/j.intimp.2010.11.001

Cited by 43 publications

(27 citation statements)

References 49 publications

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“…The potential of Treg for therapy of autoimmunity [39–42], allograft rejection [43] and graft-versus-host disease (GVHD) [9, 44–46] has been well-documented in rodent models. Although three phase I clinical trials have confirmed the safety and potential efficacy of ex vivo- expanded Treg for therapy of GVHD after hematopoietic stem cell transplantation [11, 47, 48], generation of sufficient numbers of Treg ex vivo, and development of efficacious protocols in vivo remain significant challenges.…”

Section: Discussionmentioning

confidence: 99%

Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells

Guo

Zhang

Лу

et al. 2015

Cellular Immunology

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We expanded flow-sorted Foxp3+ cynomolgus monkey regulatory T cells (Treg) >1000-fold after three rounds of stimulation with anti-CD3 mAb-loaded artificial antigen-presenting cells, rapamycin (first round only) and IL-2. The expanded Treg maintained their expression of Treg signature markers, CD25, CD27, CD39, Foxp3, Helios, and CTLA-4, as well as CXCR3, which plays an important role in T cell migration to sites of inflammation. In contrast to expanded effector T cells (Teff), expanded Treg produced minimal IFN-γ and IL-17 and no IL-2 and potently suppressed Teff proliferation. Following cryopreservation, thawed Treg were less viable than their freshly-expanded counterparts, although no significant changes in phenotype or suppressive ability were observed. Additional rounds of stimulation/expansion restored maximal viability. Furthermore, adoptively-transferred autologous Treg expanded from cryopreserved second round stocks and labeled with CFSE or VPD450 were detected in blood and secondary lymphoid tissues of normal or immunosuppressed recipients at least two months after their systemic infusion.

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Section: Discussionmentioning

confidence: 99%

Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells

Guo

Zhang

Лу

et al. 2015

Cellular Immunology

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“…7–8 However, it was postulated that Tregs need to traffic through lymphatic system to the graft site in order to provide graft immune protection. This may not be challenging after intravenous Treg infusion.…”

Section: Introductionmentioning

confidence: 99%

Improved Coating of Pancreatic Islets With Regulatory T cells to Create Local Immunosuppression by Using the Biotin-polyethylene Glycol-succinimidyl Valeric Acid Ester Molecule

Gołąb

Kızılel

Bal

et al. 2014

Transplantation Proceedings

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Background We showed that T regulatory (Treg) cells can be attached to the surface of pancreatic islets providing local immunoprotection. Further optimization of the method can improve coating efficiency, which may prolong graft survival. In this study, we compared the effectiveness of two different molecules used for binding of the Tregs to the surface of pancreatic islets. Our aim was to increase the number of Treg cells attached to islets without compromising islets viability and function. Methods Cell surface of human Treg cells and pancreatic islets was modified using biotin-polyethylene glycol (-PEG-) -N-hydroxylsuccinimide (biotin-PEG-NHS) or -succinimidyl valeric acid ester (biotin-PEG-SVA). Then, islets were incubated with streptavidin as islet/Treg cells binding molecule. Treg cells were stained with CellTracker™ CM-DiL dye and visualized using Laser Scanning Confocal Microscope. The number of Treg cells attached per islets surface area was analyzed by Imaris software. The effect of coating on islet functionality was determined using Glucose-Stimulated Insulin Response (GSIR) assay. Results Coating procedure with biotin-PEG-SVA allowed for attaching 40% more Treg cells per 1 μm2 of islets surface. While viability was comparable, function of the islets after coating using biotin-PEG-SVA molecule was better preserved than with NHS molecule. GSIR was 62% higher for islets coated with biotin-PEG-SVA compared to biotin-PEG-NHS. Conclusion Coating of islets with Treg cells using biotin-PEG-SVA improves effectiveness with better preservation of the islet function. Improvement of the method of coating pancreatic islets with Treg cells, could further facilitate the effectiveness of this novel immunoprotective approach and translation into clinical settings.

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“…In a NHP model of kidney transplantation [81], ex vivo-expanded Treg prolonged renal allograft survival in ATG-treated recipients that received numerous infusions (total=14) of expanded, donor alloAg-specific, host spleen-derived CD4 + CD25 + Treg daily (10×10 6 per day). These Treg infusions were started close to ATG administration at the time of transplant into splenectomized recipients, i.e.…”

Section: Adoptive Treg Therapy In Nonhuman Primates (Nhp)mentioning

confidence: 99%

“…Ex vivo-expanded NHP Treg [82-84] have been well-characterized, while endogenous Treg [85], as well as adoptive transfer of ex vivo-expanded Treg or anergic host T cells have been reported to suppress NHP renal allograft rejection [86, 81]. Also, the ability of Treg to suppress alloreactive effector T cell proliferation [87, 83] and their pharmacokinetics in blood and trafficking to host lymphoid tissue following adoptive transfer after lymphodepletion [88, 89] have been studied.…”

Section: Adoptive Treg Therapy In Nonhuman Primates (Nhp)mentioning

confidence: 99%

Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: the Promise and the Stumbling Blocks

Ezzelarab

Thomson

2016

Curr Transpl Rep

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The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety. The feasibility of adoptive Treg therapy in the clinic is subject to various parameters, including optimal cell source, isolation procedure, expansion, target dose, time of infusion, as well as generation of a GMP-cell product. Several phase 1/2 Treg dose-escalation studies are underway in organ transplantation. Recent evidence suggests that additional factors are critical to ensure Treg safety and efficacy in allograft recipients, including Treg characterization, stability, longevity, trafficking, concomitant immunosuppression, and donor antigen specificity. Accordingly, Treg therapy in the context of organ transplantation may prove more challenging in comparison to other prospective clinical settings of Treg immunotherapy, such as type-1 diabetes.

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Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys

Cited by 43 publications

References 49 publications

Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells

Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells

Improved Coating of Pancreatic Islets With Regulatory T cells to Create Local Immunosuppression by Using the Biotin-polyethylene Glycol-succinimidyl Valeric Acid Ester Molecule

Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: the Promise and the Stumbling Blocks

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