Ex vivo expanded human CD4+CD25+Foxp3+ regulatory T cells prevent lethal xenogenic graft versus host disease (GVHD)

Cao, Tinghua; Soto, Allis; Zhou, Wei; Wang, Weihong; Eck, Steven; Walker, Mindi; Harriman, Gregory R.; Li, Li

doi:10.1016/j.cellimm.2009.03.013

Cited by 42 publications

(38 citation statements)

References 31 publications

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“…The second novel aspect of our work is the demonstration that TRPM cells preserve their regulatory function even upon in vivo transfer into TBI-treated immunodeficient mice in the absence of any additional rapamycin treatment, thus further supporting their fixed phenotype. The in vivo suppressive potential of FOXP3 + Treg cells, freshly isolated 30 or previously expanded in the presence 31 or absence 32,33 of rapamycin, has already been shown in xeno-graft-versushost disease (GvHD) murine models. However, to our knowledge, to date no experiments have been reported in which only ex vivo-expanded Treg cells have been transferred into TBI-treated NOD/scid mice and subsequently recovered.…”

Section: Discussionmentioning

confidence: 99%

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Tresoldi¹,

Dell’Albani²,

Stabilini³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of ex vivo-expanded T-regulatory cells for the treatment of T-cell-mediated diseases has gained increasing momentum. However, the recent demonstration that FOXP3 + Tregulatory cells may contain interleukin-17-producing cells and that they can convert into effector cells once transferred in vivo raises significant doubts about their safety. We previously showed that rapamycin permits the ex vivo expansion of FOXP3 + T-regulatory cells while impairing the proliferation of non-T-regulatory cells. Here we investigated the Th17-cell content and the in vivo stability of rapamycin-expanded T-regulatory cells as pertinent aspects of cell-based therapy. Design and MethodsT-regulatory-enriched cells were isolated from healthy volunteers and were expanded ex vivo with rapamycin with a pre-clinical applicable protocol. T-regulatory cells cultured with and without rapamycin were compared for their regulatory activity, content of pro-inflammatory cells and stability. ResultsWe found that CD4+ T cells (i.e., precursor/committed Th17 cells) contaminate the T-regulatory cells cultured ex vivo in the absence of rapamycin. In addition, Th17 cells do not expand when rapamycin-treated T-regulatory cells are exposed to a "Th17-favorable" environment. Rapamycin-expanded T-regulatory cells maintain their in vitro regulatory phenotype even after in vivo transfer into immunodeficient NOD-SCID mice despite being exposed to the irradiation-induced pro-inflammatory environment. Importantly, no additional rapamycin treatment, either in vitro or in vivo, is required to keep their phenotype fixed. ConclusionsThese data demonstrate that rapamycin secures ex vivo-expanded human T-regulatory cells and provide additional justification for their clinical use in future cell therapy-based trials.Key words: T-regulatory cells, ex vivo expansion, rapamycin, cell therapy, T-regulatory-cell stability. + T regulatory cells. Haematologica 2011;96(9):1357-1365

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Section: Discussionmentioning

confidence: 99%

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Tresoldi¹,

Dell’Albani²,

Stabilini³

et al. 2011

Haematologica

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“…10 Ex vivo expansion of Tregs has been accomplished by treating purified cells with IL-2 combined with antibodies directed against CD3/CD28. 11,12 Overgrowth of effector T cells has been frequently observed after ex vivo expansion, and rapamycin has been used to reduce it. 13 Isolation and expansion of Tregs requires specialized facilities and can be challenging to obtain sufficient numbers of cells for clinical applications.…”

Section: Cd25mentioning

confidence: 99%

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Kim

Nishikii

Baker

et al. 2015

Blood

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Key Points• Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells.• T cells from DR3 antibodytreated donors result in reduced acute GVHD and preserved GVT effects. numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from aDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4 1 T cells were maintained, resulting in improved survival. Conventional T cells derived from aDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNg, IL-1b, and TNFa) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from aDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of aDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. (Blood. 2015; 126(4):546-557)

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“…To overcome this difficulty, a variety of expansion strategies have been reported [24,26,27]. In contrast, CD4 þ CD25 -T cells account for a large proportion of peripheral blood mononuclear cells (PBMCs).…”

Section: Discussionmentioning

confidence: 97%