CCL19-IgG prevents allograft rejection by impairment of immune cell trafficking.
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 TH1-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.
Ziegler
Ekkehard
E
Address correspondence to: Dr. Ulrich Kunzendorf, University of Kiel, Department of Nephrology and Hypertension, Schittenhelmstrasse 12, 24105 Kiel, Germany.
Gueler
Faikah
F
Rong
Song
S
Mengel
Michael
M
Witzke
Oliver
O
Kribben
Andreas
A
Haller
Hermann
H
Kunzendorf
Ulrich
U
Krautwald
Stefan
S
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000276:immunology; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000494:pharmacology*; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007074:Immunoglobulin G / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*
C515460:CCL19 protein, human; C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D007074:Immunoglobulin G; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins