Absence of donor CD40 protects renal allograft epithelium and preserves renal function

TY - JOUR

T1 - Absence of donor CD40 protects renal allograft epithelium and preserves renal function

AU - Kraus, Anna Katharina

AU - Cippá, Pietro Ernesto

AU - Gaspert, Ariana

AU - Chen, Jin

AU - Edenhofer, Ilka

AU - Wüthrich, Rudolph Peter

AU - Lindenmeyer, Maja

AU - Segerer, Stephan

AU - Fehr, Thomas

N1 - © 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.

PY - 2013/5

Y1 - 2013/5

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - CD40 Antigens

KW - Dendritic Cells

KW - Epithelium

KW - Kidney

KW - Kidney Transplantation

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred CBA

KW - Mice, Knockout

KW - T-Lymphocytes, Cytotoxic

KW - Th17 Cells

KW - Tissue Donors

KW - Transplantation, Homologous

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/tri.12070

DO - 10.1111/tri.12070

M3 - SCORING: Journal article

C2 - 23405964

VL - 26

SP - 535

EP - 544

JO - TRANSPL INT

JF - TRANSPL INT

SN - 0934-0874

IS - 5

ER -