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CCL19-IgG Prevents Allograft Rejection by Impairment of Immune Cell Trafficking

Ekkehard Ziegler^*, Faikah Gueler, Song Rong, Michael Mengel, Oliver Witzke, Andreas Kribben, Hermann Haller, Ulrich Kunzendorf^* and Stefan Krautwald^*

^* Department of Nephrology and Hypertension, University of Kiel, Kiel, Department of Internal Medicine and Institute for Pathology, Hannover Medical School, Hannover, and Department of Nephrology, School of Medicine, University of Duisburg-Essen, Essen, Germany

Address correspondence to: Dr. Ulrich Kunzendorf, University of Kiel, Department of Nephrology and Hypertension, Schittenhelmstrasse 12, 24105 Kiel, Germany. Phone: +49-431-597-1338; Fax: +49-431-597-1337; E-mail: kunzendorf{at}nephro.uni-kiel.de

Received for publication July 28, 2005. Accepted for publication June 23, 2006.

An adaptive immune response is initiated in the T cell area of secondary lymphoid organs, where antigen-presenting dendritic cells may induce proliferation and differentiation in co-localized T cells after T cell receptor engagement. The chemokines CCL19 and CCL21 and their receptor CCR7 are essential in establishing dendritic cell and T cell recruitment and co-localization within this unique microenvironment. It is shown that systemic application of a fusion protein that consists of CCL19 fused to the Fc part of human IgG1 induces effects similar to the phenotype of CCR7^–/– animals, like disturbed accumulation of T cells and dendritic cells in secondary lymphoid organs. CCL19-IgG further inhibited their co-localization, which resulted in a marked inhibition of antigen-specific T cell proliferation. The immunosuppressive potency of CCL19-IgG was tested in vivo using murine models for T_H1-mediated immune responses (delayed-type hypersensitivity) and for transplantation of different solid organs. In allogeneic kidney transplantation as well as heterotopic allogeneic heart transplantation in different strain combinations, allograft rejection was reduced and organ survival was significantly prolonged by treatment with CCL19-IgG compared with controls. This shows that in contrast to only limited prolongation of graft survival in CCR7 knockout models, the therapeutic application of a CCR7 ligand in a wild-type environment provides a benefit in terms of immunosuppression.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673