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Blood, 1 January 2007, Vol. 109, No. 1, pp. 244-252. Prepublished online as a Blood First Edition Paper on August 10, 2006; DOI 10.1182/blood-2006-05-021931. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-021931v1 109/1/244    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kreijveld, E. Articles by Joosten, I. Search for Related Content PubMed PubMed Citation Articles by Kreijveld, E. Articles by Joosten, I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 9, 2006 Accepted July 13, 2006 The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+CD25- T cells Ellen Kreijveld, Hans J Koenen, Luuk B Hilbrands, Hans J van Hooff, and Irma Joosten* Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Radboud University Nijmegen Medical Centre, The Netherlands Department of Internal Medicine, University Hospital Maastricht, Maastricht, the Netherlands * Corresponding author; email: i.joosten{at}abti.umcn.nl. The induction of transplantation tolerance involves a T- cell mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon TCR triggering, FK778 induced a regulatory phenotype in CD4+CD25- T cells. Purified CD4+CD25- T cells primed in the presence of FK778, showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous IL- 2 and was induced independent of naturally occurring CD4+CD25+ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778 induced anergic cells showed suppressor activity, in a cell-cell contact dependent manner, were CD25high, CD45RO+, CD27-, CD62L-, and expressed CTLA-4, GITR and FoxP3. The cells revealed delayed p27kip1 degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug FK778 shows tolerizing potential through the induction of a regulatory T cell subset in CD4+CD25- T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. A. De Serres, M. H. Sayegh, and N. Najafian Immunosuppressive Drugs and Tregs: A Critical Evaluation! Clin. J. Am. Soc. Nephrol., October 1, 2009; 4(10): 1661 - 1669. [Abstract] [Full Text] [PDF] D. Pozo, P. Anderson, and E. Gonzalez-Rey Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide J. Immunol., October 1, 2009; 183(7): 4346 - 4359. [Abstract] [Full Text] [PDF] S. Z. Josefowicz, C. B. Wilson, and A. Y. Rudensky Cutting Edge: TCR Stimulation Is Sufficient for Induction of Foxp3 Expression in the Absence of DNA Methyltransferase 1 J. Immunol., June 1, 2009; 182(11): 6648 - 6652. [Abstract] [Full Text] [PDF] X. Feng, S. Kajigaya, E. E. Solomou, K. Keyvanfar, X. Xu, N. Raghavachari, P. J. Munson, T. M. Herndon, J. Chen, and N. S. Young Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro Blood, April 1, 2008; 111(7): 3675 - 3683. [Abstract] [Full Text] [PDF]

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