title: Fc-disabled anti-mouse CD40L antibodies retain efficacy in promoting transplantation tolerance.
abstract: 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.
authors.affiliation: Therapeutic Immunology Group, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Daley
authors.forename: S P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: H
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D051381:Rats; D012867:Skin / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation / Q000379:methods*; D023001:Transplantation Tolerance
chemical_list: D007166:Immunosuppressive Agents; D023201:CD40 Ligand