| First Author | Unger LW | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 1060576 | PubMed ID | 36569922 |
| Mgi Jnum | J:334357 | Mgi Id | MGI:7413358 |
| Doi | 10.3389/fimmu.2022.1060576 | Citation | Unger LW, et al. (2022) Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen. Front Immunol 13:1060576 |
| abstractText | 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: Naive 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 alphaCD40L 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 alphaCD40L 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 alphaCD40L 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 alphaCD40L 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 alpha-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically. |
