1. ¹Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
2. ²Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
3. ³Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium
4. ⁴Bioceros, Yalelaan 46, Utrecht, The Netherlands

Correspondence: Dr I Joosten, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: i.joosten@abti.umcn.nl

⁵These authors share senior authorship.

Received 22 December 2006; Revised 31 January 2007; Accepted 2 February 2007; Published online 12 March 2007.

Abstract

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3⁺ regulatory T-cell (T_REG) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T_REG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T_REG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4⁺CD25⁺FoxP3⁺ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25⁺FoxP3⁺ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4⁺FoxP3⁺ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4⁺FoxP3⁺ T_REG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.