Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates

Abstract

CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

“…Costimulatory blockade with anti-CD40 ligand antibody (aCD40L) plus donor specific transfusion (DST) is one approach that is extremely effective in rodents and shows promise in larger animals (12)(13)(14)(15)(16). Present evidence suggests that this intervention may delete alloantigen-reactive CD8π T cells and may induce anergy and/or regulatory immunity of donor-reactive CD4π T cells (17,18).…”

Prolonged Blockade of CD40-CD40 Ligand Interactions by Gene Transfer of CD40Ig Results in Long-Term Heart Allograft Survival and Donor-Specific Hyporesponsiveness, But Does Not Prevent Chronic Rejection

“…Blockade of CD40-CD40L interactions by the use of anti-CD40L mAbs in mice (12)(13)(14)(15)(16)(17)(18) and primates (19,20) has resulted in prolongation of allograft survival. However, in only some of these studies, a fraction of the recipients showed long-term engraftment (12,17,19,20).…”

Lack of Role for CsA‐Sensitive or Fas Pathways in the Tolerization of CD4 T Cells Via BMT and Anti‐CD40L

“…All chimeric WT animals accepted donor skin grafts >200 days (top), while rejecting third party grafts (bottom), whereas all Bcl-x L recipient mice rejected both donor and third party grafts. (2,39,40), has been reported to be detrimental to the prolongation of graft survival in various protocols using costimulatory blockade (2,21,22). One critical function of calcineurin is the dephosphorylation and activation of NFAT, a key transcription factor involved in the production of IL-2 (41), which promotes FAS-mediated AICD by down-regulating the amount of FLIP, the down-regulator of apoptosis, associated with the Fas molecule (36).…”

“…Fas) signals to the T cell [reviewed in (18)]. Data involving costimulatory blockade protocols have also suggested a role for both pathways of T-cell apoptosis in the establishment of peripheral tolerance (2,15,19,20) and impairment of graft prolongation has been reported in recipients in which AICD is blocked by calcineurin inhibitors (2,21,22). Therefore, it is important to understand the role of each type of apoptosis in the induction of lasting chimerism and tolerance using costimulatory blockade and BMT.…”