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Updated: May 14, 2026
In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
Published on: August 12, 2017
Absence of donor CD40 protects renal allograft epithelium and preserves renal function
Anna Katharina Kraus1, Pietro Ernesto Cippá, Ariana Gaspert
1Institute of Physiology, University of Zurich, Zurich, Switzerland.
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.
Insights
Blocking donor CD40, not CD154, prevents kidney transplant rejection. This strategy reduces T-cell responses and protects kidney cells, improving allograft function without thromboembolic risks.
Area of Science:
- Immunology
- Transplantation Biology
- Renal Medicine
Background:
- The CD40-CD154 pathway is crucial for immune responses, but CD154 blockade causes thromboembolic complications.
- Blocking CD40 is an alternative strategy to prevent allograft rejection and induce tolerance.
- Donor CD40's role in T-cell responses and allograft outcomes requires further investigation.
Purpose of the Study:
- To investigate the impact of donor CD40 deficiency on T-cell responses and renal allograft function.
- To elucidate the mechanisms by which donor CD40 influences allospecific T-cell differentiation, particularly Th17 cells.
- To assess the potential of targeting donor CD40 for improving kidney transplant outcomes.
Main Methods:
- In vitro assays to assess T-cell proliferation and differentiation in response to donor CD40.
- In vivo renal transplantation model using fully MHC-mismatched CD40-deficient and wild-type donors.
- Assessment of renal function, apoptosis in tubular epithelial cells, and PD-L1 expression in allografts.
Main Results:
- Allografts from CD40-deficient donors showed improved renal function compared to wild-type.
- Reduced apoptosis and increased PD-L1 expression were observed in renal tubular epithelial cells of CD40-deficient allografts.
- Donor CD40 deficiency critically impaired the induction of Th17 cells, both in vitro and in vivo.
Conclusions:
- Donor CD40 plays a critical role in initiating direct allospecific T-cell responses, especially Th17 differentiation.
- Targeting donor CD40 may protect renal tubular epithelium from apoptosis and preserve kidney allograft function.
- CD40 blockade represents a promising strategy for improving kidney transplantation outcomes by mitigating immune responses and protecting the graft.
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01:28Kidney Transplant I: Introduction
01:26Kidney Transplant II: Surgical Procedure
01:40Cell-mediated Immune Responses