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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 gamma2b 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.

Original publication

DOI

10.1111/j.1600-6143.2008.02382.x

Type

Journal article

Journal

Am J Transplant

Publication Date

11/2008

Volume

8

Pages

2265 - 2271

Keywords

Animals, Blood Platelets, Bone Marrow Transplantation, CD40 Ligand, Female, Glycosylation, Immunosuppressive Agents, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Rats, Skin, Skin Transplantation, Transplantation Tolerance