| Sumari: | <p>Clinical transplantation continues to rely on the use of non-specific immunosuppressive therapy, which reduces the incidence of graft rejection but also carries with it undesirable side effects such as infection and malignancy. A preferable option would be to induce operational graft tolerance without the need for such non-specific therapy, for example by harnessing natural mechanisms. In recent years there has been much progress in the characterisation of CD4<sup>+</sup> cells that possess suppressive or regulatory properties in experimental systems; particular attention has been focussed upon CD4<sup>+</sup> cells expressing CD25, the α subunit of the IL-2 receptor, which have been shown to possess regulatory capacity both <em>in vitro</em> and <em>in vivo</em> in autoimmune disease and transplantation models. The aim of this study was to examine the potential role of CD4<sup>+</sup>CD25<sup>+</sup> regulatory T cells (Treg) in the induction phase of tolerance in a transplantation model.</p> <p>Pre-treatment of mice with fully allogeneic blood administered under the cover of anti-CD4 antibody is shown to lead to the generation of CD4<sup>+</sup>CD25<sup>+</sup> cells capable of preventing the rejection of donor type, but not third party, skin allografts mediated by CD4<sup>+</sup>CD45RB<sup>high</sup> cells in secondary recipients. In addition to their suppressive properties <em>in vivo</em>, these CD4<sup>+</sup>CD25<sup>+</sup> cells also display the ability to regulate the proliferation of target T cell populations <em>in vitro</em>.</p> <p>Generation of CD4<sup>+</sup>CD25<sup>+</sup> Treg by the pre-treatment protocol is not reliant upon an intrathymic selection process nor upon the expansion of a pre-existing CD4<sup>+</sup>CD25<sup>+</sup> Treg population, but can occur through the conversion of peripheral CD4<sup>+</sup>CD25<sup>-</sup> cells to a regulatory phenotype.</p> <p>Although the regulatory function of the CD4<sup>+</sup>CD25<sup>+</sup> cells generated by pre-treatment is donor strain-specific <em>in vivo</em>, this specificity can be overcome by activating the cells before their regulatory capacity is tested. Moreover, CD4<sup>+</sup>CD25<sup>+</sup> cells generated by pre-treatment with a non-cellular protein antigen completely unrelated to the graft can also regulate skin allograft rejection provided that these Treg are first activated.</p> <p>It is hoped that the principles defined by these findings identify a strategy that may be applicable in clinical transplantation and in the therapy of autoimmune disease.</p>
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