Author(s): David F Pinelli [*] aff1 , Mandy L Ford aff1
CD40; CD40L; costimulation; Fc receptor; thromboembolism; transplantation
A myriad of studies over the past two decades have revealed the importance of CD40-CD154 interactions in the generation of alloreactive responses, and as such it represents an extremely attractive target for therapeutic intervention in transplantation. This pathway requires the interaction of the CD40 molecule with its ligand, CD40L (CD154). These molecules belong to the TNF superfamily and are expressed on a wide range of tissues and cell types, with CD40 constitutively expressed on APC, including B cells, macrophages and dendritic cells (DCs), and CD154 inducibly expressed mainly on CD4+ T cells and endothelial cells following activation [1 ]. The first descriptions of this pathway focused on the importance of CD40-CD154 interactions in promoting T-cell-dependent humoral responses [ 2 ], but it quickly became apparent that these interactions were also essential for generating cell-mediated immunity. Seminal studies showed that the cross-linking of CD40 on DCs by CD154 on activated CD4+ helper T cells led to 'licensing' of the APC, leading to the upregulation of the B7 family of costimulatory molecules and the elaboration of proinflammatory cytokines [3,4 ]. More recent studies have also suggested that the interaction of CD154 on activated CD4+ T cells and CD40 on CD8+ T cells also plays a critical role in generating effective cytotoxic T-cell responses [5 ].
The potent immunostimulatory effects of CD40-CD154 interactions make it one of the most attractive targets for immunomodulatory therapy. A number of preclinical rodent and nonhuman primate studies in islet and solid organ transplantation showed the dramatic efficacy of targeting this pathway with anti-CD154 monoclonal antibodies [6-8 ], and thus several clinical trials were initiated to test their efficacy in autoimmune disease and transplantation. Three separate antibodies - ruplizumab, toralizumab and ABI793 - were developed and tested, but in a number of these trials patients experienced thromboembolic complications (reviewed in [9 ]). Several groups attempted to confirm these results in nonhuman primate studies, with some reports confirming the thrombogenic properties of anti-CD154 antibodies [10 ], while other studies saw no evidence of thromboembolism [11 ]. Other reports suggested that agents coadministered with anti-CD154, such as calcium chloride, may have been responsible for adverse events [ 12 ]. However, given the recurrence of thromboembolism during multiple trials with anti-CD154 antibodies that bound distinct epitopes of CD154, many groups sought to elucidate the mechanism by which anti-CD154 therapy led to these adverse events.
CD40 and CD154 are expressed on endothelial cells and activated platelets, respectively, and while CD40-CD154 interactions have been shown to play a role in thrombus stabilization and platelet activation [13 ], the exact nature of the required interactions is still somewhat unclear. Indeed, unequivocal evidence of the mechanism linking anti-CD154 therapy-related thromboembolism to expression of CD154 on platelets was still lacking. Several studies have investigated the potential of CD154 to interact with molecules distinct from its classical interaction with CD40 and the possible role of these interactions in the etiology...