Identification, selection, and expansion of non-gene modified alloantigen-reactive Tregs for clinical therapeutic use

Alzhrani, Alaa; Bottomley, Matthew J.; Wood, Kathryn J.; Hester, Joanna; Issa, Fadi

doi:10.1016/j.cellimm.2020.104214

Cited by 23 publications

(17 citation statements)

References 75 publications

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“…Some challenges were associated with the clinical protocol, and its applicability was dependent on the delay in patient recruitment and cell infusion at least 6 months post-transplant. Prospective investigations should optimize this approach alone or in combination with lymphodepletive therapies to attenuate or even wean off immunosuppressive drugs following liver transplantation ( 127 ).…”

Section: Role In Transplantationmentioning

confidence: 99%

“…Their inability to persist in high numbers in the circulation may reflect the increased rate of apoptosis associated with low IL-2 availability or preferential migration into peripheral tissues. This challenge may be addressed by long-term tracking the injected cells via a novel non-invasive imaging technology in the future ( 127 ).…”

Section: Role In Transplantationmentioning

confidence: 99%

“…Despite the limited but promising success of polyclonal Tregs, infusion required a large number of cells, and the threat of non-specific immunosuppression is possible ( 126 ). To successfully deal with these restrictions, both required high cell numbers as well as the off-target specificity of polyclonal Tregs, an enriched population of alloantigen-specific Tregs could be used ( 127 ).…”

Section: Role In Transplantationmentioning

confidence: 99%

“…Preliminary B cell expansion and activation steps are vitally important in using B cell for Treg allostimulation. Since B cell proliferation requires a costimulatory signal from CD40/CD40L, CD40L-expressing fibroblasts have been used as feeder cells for B cell expansion ( 127 ). As compliance with Good Manufacturing Process (GMP) in this method is mandatory for donor material to be collected, it is considered a limitation for this approach.…”

Section: Role In Transplantationmentioning

confidence: 99%

“…Considering that no scientific research has been conducted to directly compare expansion utilizing stimulatory cell populations as an alternative from the same donor, it is still inconclusive which approach would be the most effective for generating alloantigen specific Tregs ( 127 ). In 2016, Todo, et al reported the use of alloantigen specific Tregs generated in living donor liver transplantation ( 137 ).…”

Section: Role In Transplantationmentioning

confidence: 99%

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The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities

et al. 2021

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Regulatory T cells (Tregs) are an immunosuppressive subgroup of CD4+ T cells which are identified by the expression of forkhead box protein P3 (Foxp3). The modulation capacity of these immune cells holds an important role in both transplantation and the development of autoimmune diseases. These cells are the main mediators of self-tolerance and are essential for avoiding excessive immune reactions. Tregs play a key role in the induction of peripheral tolerance that can prevent autoimmunity, by protecting self-reactive lymphocytes from the immune reaction. In contrast to autoimmune responses, tumor cells exploit Tregs in order to prevent immune cell recognition and anti-tumor immune response during the carcinogenesis process. Recently, numerous studies have focused on unraveling the biological functions and principles of Tregs and their primary suppressive mechanisms. Due to the promising and outstanding results, Tregs have been widely investigated as an alternative tool in preventing graft rejection and treating autoimmune diseases. On the other hand, targeting Tregs for the purpose of improving cancer immunotherapy is being intensively evaluated as a desirable and effective method. The purpose of this review is to point out the characteristic function and therapeutic potential of Tregs in regulatory immune mechanisms in transplantation tolerance, autoimmune diseases, cancer therapy, and also to discuss that how the manipulation of these mechanisms may increase the therapeutic options.

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Section: Role In Transplantationmentioning

confidence: 99%

Section: Role In Transplantationmentioning

confidence: 99%

Section: Role In Transplantationmentioning

confidence: 99%

Section: Role In Transplantationmentioning

confidence: 99%

Section: Role In Transplantationmentioning

confidence: 99%

See 3 more Smart Citations

The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities

et al. 2021

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Biomaterial‐Based Therapeutic Delivery of Immune Cells

Dravid,

Singh,

García

2024

Adv Healthcare Materials

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Immune cell therapy is a transformative approach used to treat a wide range of diseases including type 1 diabetes, sickle cell disease, disorders of the hematopoietic system, and certain forms of cancers. Despite excellent clinical successes, the scope of adoptively transferred immune cells is limited because of toxicities like cytokine release syndrome and immune effector cell‐associated neurotoxicity in patients. Furthermore, reports suggest that such treatment can impact major organ systems including cardiac, renal, pulmonary, and hepatic systems in the long term. Additionally, adoptively transferred immune cells cannot achieve significant penetration into solid tissues, thus limiting their therapeutic potential. Recent studies suggest that biomaterial‐assisted delivery of immune cells can address these challenges by reducing toxicity, improving localization, and maintaining desired phenotypes to eventually regain tissue function. In this review, we highlight recent efforts in the field of biomaterial‐based immune cell delivery for the treatment of diseases, their pros and cons, and where these approaches stand in terms of clinical treatment.This article is protected by copyright. All rights reserved

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Chimeric antigen receptor‐modified human regulatory T cells that constitutively express IL‐10 maintain their phenotype and are potently suppressive

et al. 2021

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Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.

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Identification, selection, and expansion of non-gene modified alloantigen-reactive Tregs for clinical therapeutic use

Cited by 23 publications

References 75 publications

The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities

The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities

Biomaterial‐Based Therapeutic Delivery of Immune Cells

Chimeric antigen receptor‐modified human regulatory T cells that constitutively express IL‐10 maintain their phenotype and are potently suppressive

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