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Allosuppressive Donor CD4⁺CD25⁺ Regulatory T Cells Detach from the Graft and Circulate in Recipients after Liver Transplantation¹

Ahmet Demirkiran^*, Brenda M. Bosma, Alice Kok^*, Carla C. Baan, Herold J. Metselaar, Jan N. M. IJzermans^*, Hugo W. Tilanus^*, Jaap Kwekkeboom and Luc J. W. van der Laan^2,*

^* Department of Surgery, Department of Gastroenterology and Hepatology, and Department of Internal Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands

Organ transplantation (Tx) results in a transfer of donor leukocytes from the graft to the recipient, which can lead to chimerism and may promote tolerance. It remains unclear whether this tolerance involves donor-derived regulatory T cells (Tregs). In this study, we examined the presence and allosuppressive activity of CD4⁺CD25⁺Foxp3⁺ Tregs in perfusates of human liver grafts and monitored the cells presence in the circulation of recipients after liver Tx. Vascular perfusions of 22 liver grafts were performed with University of Wisconsin preservation and albumin solutions. Flow cytometric analysis revealed that perfusate T cells had high LFA-1 integrin expression and had a reversed CD4 to CD8 ratio compared with control blood of healthy individuals. These findings indicate that perfusate cells are of liver origin and not derived from residual donor blood. Further characterization of perfusate mononuclear cells showed an increased proportion of CD4⁺CD25⁺CTLA4⁺ T cells compared with healthy control blood. Increased percentages of Foxp3⁺ cells, which were negative for CD127, confirmed the enrichment of Tregs in perfusates. In MLR, CD4⁺CD25⁺ T cells from perfusates suppressed proliferation and IFN- production of donor and recipient T cells. In vivo within the first weeks after Tx, up to 5% of CD4⁺CD25⁺CTLA4⁺ T cells in recipient blood were derived from the donor liver. In conclusion, a substantial number of donor Tregs detach from the liver graft during perfusion and continue to migrate into the recipient after Tx. These donor Tregs suppress the direct pathway alloresponses and may in vivo contribute to chimerism-associated tolerance early after liver Tx.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by unrestricted grants from the Revolving Fund and Translational Fund of the Erasmus MC-University Medical Center Rotterdam and the Gastrostart Fund from the Dutch Society of Gastroenterology and Hepatology.

² Address correspondence and reprint requests to Dr. Luc J. W. van der Laan, Department of Surgery, Erasmus MC-University Medical Center, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E-mail address: l.vanderlaan{at}erasmusmc.nl

³ Abbreviations used in this paper: Tx, transplantation; Foxp3, forkhead box p3; LPMC, liver perfusate mononuclear cell; Treg, regulatory T cell; DC, dendritic cell.