CD40L antibodies have proven to be powerful immunosuppressive agents in nonhuman primates but unfortunately perturb blood coagulation. Neither the therapeutic nor the prothrombotic mechanism of anti-CD40L is defined sufficiently to determine whether these effects can be uncoupled. Recent evidence suggests that the Fc region of anti-CD40L antibodies interacting with Fc receptors plays an important role in stabilizing platelet aggregates. An Fc-disabled, aglycosylated anti-CD40L heavy chain variant was therefore created to determine whether it might still be useful in promoting transplantation tolerance. In a number of mouse models an engineered aglycosyl anti-CD40L recapitulated the effects of the intact anti-CD40L antibody in tolerance protocols involving transplantation of allogeneic bone marrow and skin. In contrast, another anti-CD40L variant with a conventional rat γ2b heavy chain was less effective in ensuring long-term skin graft survival, possibly associated with its faster clearance from the circulation. These results show that short pulses of anti-CD40L antibody therapy may still be useful in tolerance protocols even when the Fc region is disabled.
- Allograft tolerance
- Anti-CD154 monoclonal antibody
- Transplant immunology
- Transplant tolerance
- Venous thromboembolism