Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen

Abstract

IntroductionIn 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.MethodsNaïve 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 DiscussionAdministering 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.

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

“…1d ). We then combined ATG with a previously described CTLA4-Ig maintenance treatment that was modeled after the clinically approved dosing regimen 24 , 25 , 29 , employing a fully mismatched, relatively costimulation blockade-resistant donor-recipient strain combination (BALB/c to B6) 30 , 31 (Fig. 1a ).…”

“…With this current study, we sought to delineate the mechanisms responsible for the failure of ATG induction, which is effective in reducing rejection rates when used with CNIs, to control costimulation blockade-resistant rejection 20,21 . Using a mouse heart transplant model of CTLA4-Ig maintenance therapy 24,25,29 , we found that ATG fails to improve the Treg: Teff balance within the allograft, which is improved only in the peripheral compartment. Cytokine measurements pointed to elevated serum IL-6 levels as a potential cause for the lack of ATG efficacy.…”