Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision

Adair, Patrick; Kim, Yong Chan; Zhang, Aihong; Yoon, Jeongheon; Scott, David W.

doi:10.3389/fimmu.2017.01117

Cited by 34 publications

(29 citation statements)

References 110 publications

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“…Investigators have also considered the construction of T reg cells with a TCR that recognizes factor VIII in order to suppress the production of neutralizing antibodies in patients with haemophilia 181 ; these patients often develop immune responses to injected factor VIII. These proof-of-concept studies pave the way to clinical evaluation of CAR T reg cells in humans.…”

Section: Antigen-specific T Reg Cell Therapiesmentioning

confidence: 99%

Regulatory T cells in the treatment of disease

Sharabi

Tsokos

Ding

et al. 2018

Nat Rev Drug Discov

252

206

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| Regulatory T (T reg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, T reg cells are compromised. Approaches to strengthen T reg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing T reg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, T reg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of T reg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating T reg cells in autoimmune disorders, transplantation and cancer.

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Section: Antigen-specific T Reg Cell Therapiesmentioning

confidence: 99%

Regulatory T cells in the treatment of disease

Sharabi

Tsokos

Ding

et al. 2018

Nat Rev Drug Discov

252

206

View full text Add to dashboard Cite

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“…The adoptive transfer of antigen-specific Tregs was shown to be a more promising approach because fewer cells are needed to suppress targeted cells, which reduces the risk of nonspecific immunosuppression (9,10). There are several strategies to generate antigen-specific Tregs, which overexpress a transgenic T cell receptor (TCR) or expand when stimulated with antigen.…”

Section: Introductionmentioning

confidence: 99%

CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD

et al. 2020

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“…The use of efficient antigen-specific Tregs may reduce the number of Tregs required for therapy and lower the risk of systemic immunosuppression ( 25 , 26 ). Numerous studies have investigated strategies for large-scale expansion of alloantigen-specific human Tregs ( 27 – 29 ), and ex vivo alloantigen-specific Tregs were shown to possess enhanced suppressive capacity in allogeneic responses in vitro and in vivo ( 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

Adoptive transfer of xenoantigen‑stimulated T cell receptor Vβ‑restricted human regulatory T cells prevents porcine islet xenograft rejection in humanized mice

Jin

Gong

et al. 2018

Mol Med Report

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Polyclonal expansion of human regulatory T cells (Tregs) prevents xenogeneic rejection by suppressing effector T cell responses in vitro and in vivo. However, a major limitation to using polyclonally expanded Tregs is that they may cause pan-immunosuppressive effects. The present study was conducted to compare the ability of ex vivo expanded human xenoantigen-stimulated Tregs (Xeno-Treg) and polyclonal Tregs (Poly-Treg) to protect islet xenografts from rejection in NOD-SCID interleukin (IL)-2 receptor (IL2r)γ−/− mice. Human cluster of differentiation (CD)4+CD25+CD127lo Tregs, expanded either by stimulating with porcine peripheral blood mononuclear cells (PBMCs) or anti-CD3/CD28 beads, were characterized by immune cell phenotyping, T cell receptor (TCR) Vβ CDR3 spectratyping and performing suppressive activity assays in vitro. The efficiency of adoptively transferred ex vivo human Tregs was evaluated in vivo using neonatal porcine islet cell clusters (NICC) transplanted into NOD-SCID IL-2rγ−/− mice, which received human PBMCs with or without Xeno-Treg or Poly-Treg. Xeno-Treg, which expressed increased levels of human leukocyte antigen-DR and secreted higher levels of IL-10, demonstrated enhanced suppressive capacity in a pig-human mixed lymphocyte reaction. Spectratypes of TCR Vβ4, Vβ10, Vβ18 and Vβ20 in Xeno-Treg showed restriction and expanded clones at sizes of 205, 441, 332 and 196 respectively, compared to those of Poly-Treg. Reconstitution of mice with human PBMCs and Poly-Treg resulted in NICC xenograft rejection at 63 days. Adoptive transfer with human PBMCs and Xeno-Treg prolonged islet xenograft survival beyond 84 days, with grafts containing intact insulin-secreting cells surrounded by a small number of human CD45+ cells. This study demonstrated that adoptive transfer of ex vivo expanded human Xeno-Treg may potently prevent islet xenograft rejection in humanized NOD-SCID IL2rγ−/− mice compared with Poly-Treg. These findings suggested that adoptive Treg therapy may be used for immunomodulation in islet xenotransplantation by minimizing systemic immunosuppression.

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Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision

Cited by 34 publications

References 110 publications

Regulatory T cells in the treatment of disease

Regulatory T cells in the treatment of disease

CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD

Adoptive transfer of xenoantigen‑stimulated T cell receptor Vβ‑restricted human regulatory T cells prevents porcine islet xenograft rejection in humanized mice

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