title: Absence of donor CD40 protects renal allograft epithelium and preserves renal function.
abstract: Blocking the CD40-CD154 pathway prevents allograft rejection and induces donor-specific tolerance in various experimental models. However, the translation to clinical studies has been hampered by unexpected thromboembolic complications of CD154-blocking antibodies. Thus, blocking CD40 instead is now considered as an alternative strategy. Here, we evaluated the role of donor CD40 in allospecific T-cell responses in vitro and in an in vivo model for renal transplantation. Fully MHC-mismatched allografts from CD40-deficient donors displayed better renal function than wild type. These functional data correlated with a lower level of apoptosis in renal tubular epithelial cells and higher expression of PD-L1, which is most probably because of a reduced Th17 response in recipients of a CD40-deficient donor. This hypothesis was supported in vitro, where donor CD40 expression was important for the induction of direct allospecific T-cell responses. Especially the induction of Th17 cells was critically dependent on donor CD40. IL-17A in conjunction with interferon-γ in turn rendered renal tubular epithelial cells to a more costimulatory state by upregulating CD40 and downregulating PD-L1 expression. In conclusion, CD40 blockade not only reduces the allospecific T-cell responses, but might also lead to protection of tubular epithelium from apoptosis and thereby preserve kidney allograft function.
authors: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors: Anna Katharina
authors: AK
authors: Kraus
authors: Pietro Ernesto
authors: PE
authors: Cippá
authors: Ariana
authors: A
authors: Gaspert
authors: Jin
authors: J
authors: Chen
authors: Ilka
authors: I
authors: Edenhofer
authors: Rudolph Peter
authors: RP
authors: Wüthrich
authors: Maja
authors: M
authors: Lindenmeyer
authors: Stephan
authors: S
authors: Segerer
authors: Thomas
authors: T
authors: Fehr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D019013:CD40 Antigens / Q000172:deficiency* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000502:physiology; D016030:Kidney Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D019013:CD40 Antigens