Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans

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Abstract
Regulatory T cells represent a distinct T-cell subset that has a key role in inducing and maintaining immunological tolerance. Several different regulatory T-cell subsets have been described. This Review focuses on forkhead box P3 (FOXP3)+CD4+CD25+ T cells, being the only natural occurring regulatory T-cell subset described so far, and on T regulatory type 1 cells, being the only inducible subset used in the clinic to date. Compelling data generated in preclinical animal models indicate that regulatory T cells can be used as therapeutic agents for inducing tolerance to alloantigens after transplantation or for re-establishing self-tolerance in autoimmune diseases. The possibility that human regulatory T cells might have an application for the treatment of T-cell-mediated diseases has recently gained increasing momentum. However, it is still unclear: which regulatory T-cell subset is most appropriate for adoptive transfer; which method should be used for their ex vivo expansion or differentiation; which human disease would benefit the most from regulatory T-cell transfer; and whether a combined therapy with other drugs will be needed. At present, a few clinical trials of human regulatory T-cell-based immunotherapy are ongoing after bone-marrow transplantation. These trials will hopefully pave the way for the application of this therapy to other immune-mediated diseases. The common future clinical application of regulatory T-cell-based immunotherapy strongly depends on safety, ethical and economical issues. This therapeutic approach must be safe and prove to be of superior efficacy over conventional therapy. Furthermore, in its initial experimental phase, regulatory T-cell-based immunotherapy is extremely expensive and requires good manufacturing practice certified facilities. Should this immunotherapy meet its therapeutic target, one could envisage that not only academic institutions but also pharmaceutical companies will be interested in adopting this therapeutic approach.