Hurdles in therapy with regulatory T cells

Trzonkowski, Piotr; Bacchetta, Rosa; Battaglia, Manuela; Berglund, David; Bohnenkamp, H; Brinke, Anja ten; Bushell, Andrew; Cools, Nathalie; Geissler, Edward K.; Gregori, Silvia; Ham, S. Marieke van; Hilkens, Catharien M. U.; Hutchinson, James A.; Lombardi, Giovanna; Madrigal, J. Alejandro; Marek-Trzonkowska, Natalia; Martı́nez-Cáceres, Eva; Roncarolo, Maria Grazia; Sánchez‐Ramón, Silvia; Saudemont, Aurore; Sawitzki, Birgit

doi:10.1126/scitranslmed.aaa7721

Cited by 137 publications

(128 citation statements)

References 61 publications

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“…Based on what has been described in transplantation clinical trials, the function and application of huTregs are quite promising. Until now, it has been possible to generate protocols for the purification and expansion of huTregs from healthy donors and patients, with the following infusion for treating conditions as transplant rejection, GvHD or autoimmune diseases [1,2,4,20].…”

Section: Discussionmentioning

confidence: 99%

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IL-33 improves the suppressive capacity of human regulatory T cells

Gajardo¹,

Campos‐Mora²,

Pino‐Lagos³

2017

Trends in Transplant

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One of the main problems that immunologists have not solved yet involves the immunosuppression of ongoing exacerbated responses, as in transplant rejection and autoimmune diseases. To overcome these difficulties, different approaches have been used including the administration of immunosuppressive drugs, monoclonal antibodies, and more recently, the utilization of cellular therapy. In this last strategy, huTregs have been proposed as a safe tool to control transplant rejection or collateral immune reactions such as GvHD. Tregs are a subtype of CD4+ T cells characterized by the expression of markers such as CD25, CD127, Foxp3, among others, and their capacity to induce immune tolerance. For this reason, huTregs have become an attractive target for their manipulation and application in the clinic. In this work, we used an established protocol for the expansion of peripheral blood-derived huTregs, adding IL-33 as a putative enhancer of huTregs function, due to its previously identified capacity for driving transplant tolerance. Here, we characterized the phenotype, expansion rate and suppressive function of huTregs 33 . Although IL-33 did not modify the expression of Tregs canonical markers nor their proliferative activity, it did potentiate their suppressive function. This remarkable observation may be driven in part by the up-regulation of the immune regulatory-related genes, Foxp3, Amphiregulin and ST2. Thus, huTregs 33 should be considered for pre-clinical and clinical studies.

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Section: Discussionmentioning

confidence: 99%

“…In contrast to murine Tregs, huTregs correspond to 5% of Peripheral blood mononuclear cells (PBMC) and express the surface markers CD4, CD25 and low/negative expression of CD127, and transcription factor Forkhead-box P3 (FoxP3), characteristic of murine and human Tregs [1].…”

Section: Introductionmentioning

confidence: 99%

IL-33 improves the suppressive capacity of human regulatory T cells

Gajardo¹,

Campos‐Mora²,

Pino‐Lagos³

2017

Trends in Transplant

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“…As such, various groups developed protocols for isolating and expanding autologous human Tregs [14,23,27]. However, the lack of a definitive human Treg marker and the requirement for compliance with good manufacturing practice (GMP) has meant that Treg therapy is only now moving from the bench to the clinic [14,23,27].…”

Section: Regulatory T-cell Therapy -Current Applicationsmentioning

confidence: 99%

Antigen-specificity using chimeric antigen receptors: the future of regulatory T-cell therapy?

Boardman

Maher

Lechler

et al. 2016

Biochemical Society Transactions

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Adoptive regulatory T-cell (Treg) therapy using autologous Tregs expandedex vivois a promising therapeutic approach which is currently being investigated clinically as a means of treating various autoimmune diseases and transplant rejection. Despite this, early results have highlighted the need for potent Tregs to yield a substantial clinical advantage. One way to achieve this is to create antigen-specific Tregs which have been shown in pre-clinical animal models to have an increased potency at suppressing undesired immune responses, compared to polyclonal Tregs. This mini review outlines where Treg therapy currently stands and discusses the approaches which may be taken to generate antigen-specific Tregs, including the potential use of chimeric antigen receptors (CARs), for future clinical trials.

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“…Several studies showed promising results using adoptive Tregs (67)(68)(69)(70)(71)(72)(73)(74). However, before adoptive Treg therapy is a cellular therapeutic agent, there are various hurdles to overcome (75). We need to identify and isolate Tregs, and expand them under good manufacturing practice for cellular product manufacturing.…”

Section: How To Incorporate Moga In Transplant-eligible Patients Withmentioning

confidence: 99%