Absence of donor CD40 protects renal allograft epithelium and preserves renal function |
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Authors: | Anna Katharina Kraus Pietro Ernesto Cippá Ariana Gaspert Jin Chen Ilka Edenhofer Rudolph Peter Wüthrich Maja Lindenmeyer Stephan Segerer Thomas Fehr |
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Institution: | 1. Institute of Physiology, University of Zurich, , Zurich, Switzerland;2. Division of Nephrology, University Hospital Zurich, , Zurich, Switzerland;3. Institute of Surgical Pathology, University Hospital Zurich, , Zurich, Switzerland;4. Institute of Anatomy, University of Zurich, , Zurich, Switzerland |
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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. |
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Keywords: | CD40 costimulation renal allograft renal tubular cells Th17 |
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