Related Experiment Video
Updated: Aug 16, 2025
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
Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig
Lukas W Unger1,2, Moritz Muckenhuber1, Benedikt Mahr1
1Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
Insights
Combining CTLA4-Ig and CD40L blockade therapy can achieve long-term heart allograft survival. Chronic administration of both agents, alongside permanent CD40-CD40L signaling interruption, is crucial for preventing rejection and preserving graft integrity without donor-specific antibodies.
Area of Science:
- Transplantation immunology
- Immunosuppression strategies
- Allograft rejection mechanisms
Background:
- Belatacept (CTLA4-Ig) improves kidney graft function but increases acute rejection risk.
- Combining costimulation blockers may enhance outcomes and avoid calcineurin inhibitor toxicity.
Purpose of the Study:
- To define conditions for rejection-free, permanent graft survival using CTLA4-Ig and CD40L blockade.
- To investigate synergistic effects in a stringent murine heart transplantation model.
Main Methods:
- Utilized a fully mismatched BALB/c cardiac allograft in naïve wild-type or CD40L knockout mice.
- Investigated induction and maintenance protocols for CTLA4-Ig and anti-CD40L monoclonal antibodies (mAB).
- Assessed graft survival, rejection severity, and donor-specific antibody (DSA) formation over 100 days.
Main Results:
- Monotherapy with anti-CD40L mAB prolonged allograft survival but showed no added benefit with chronic CTLA4-Ig.
- Chronic anti-CD40L mAB with perioperative CTLA4-Ig resulted in rejection and histological damage, despite abrogating DSA.
- Permanent interruption of CD40-CD40L signaling synergized with chronic CTLA4-Ig for long-term survival, preserved graft integrity, and prevented DSA.
Conclusions:
- Chronic administration of both CTLA4-Ig and anti-CD40L is most effective for long-term allograft survival.
- Permanent interruption of CD40-CD40L signaling combined with chronic CTLA4-Ig achieves rejection-free survival and preserves graft histology.
- This combination therapy offers a promising strategy for preventing allograft rejection and DSA formation.
Introduction:
In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.
Methods:
Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.
Results And Discussion:
Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.
