title: Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells.
abstract: Deficiency of transplant recipients for the chemokine receptor CCR7 was originally described to slightly increase the survival time of vascularized solid organ grafts, probably due to a reduced priming of alloreactive T cells. Using a model of allotolerance induction by donor-specific splenocyte transfusion (DST) in combination with anti-CD40L mAb-mediated costimulation blockade (CSB), we show here a striking failure of CCR7-deficient (CCR7(-/-) ) recipients to tolerate cardiac allografts. Furthermore, in addition to the recently described lack of Treg, CCR7(-/-) mice were found to harbor significantly reduced numbers of plasmacytoid dendritic cells (pDCs) within peripheral as well as mesenteric lymph nodes (LNs), but not the bone marrow or spleen. pDCs had previously been suggested to function as tolerogenic APC during allograft transplantation, and a single transfer of syngeneic WT pDCs, but not conventional DCs, was indeed sufficient to rescue graft survival in DST+CSB-treated CCR7(-/-) recipients in a dose-dependent manner. We therefore conclude that the nearly complete absence of pDCs within LNs of CCR7(-/-) mice prevents the successful induction of DST+CSB-mediated allotolerance, leading to the observed acute rejection of cardiac allografts under tolerizing conditions.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Xiaosun
authors.initials: X
authors.lastname: Liu
authors.forename: Pooja
authors.initials: P
authors.lastname: Mishra
authors.forename: Songfeng
authors.initials: S
authors.lastname: Yu
authors.forename: Jan
authors.initials: J
authors.lastname: Beckmann
authors.forename: Meike
authors.initials: M
authors.lastname: Wendland
authors.forename: Jessica
authors.initials: J
authors.lastname: Kocks
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seth
authors.forename: Katharina
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
authors.forename: Tim
authors.initials: T
authors.lastname: Worbs
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014019:Tissue Donors; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D000911:Antibodies, Monoclonal; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D023201:CD40 Ligand