Blocking antibodies specific for CD154 (also known as CD40L) can prevent allograft rejection, and it is thought that this is a result of impaired interactions between T cells and antigen-presenting cells (APCs). However, compared with other antibodies that inhibit T-cell activation, very high levels of CD154-specific antibodies are required to prevent allograft rejection. Now, in a study published in The Journal of Clinical Investigation, it is shown that soluble CD154 derived from activated platelets can induce cardiac allograft rejection, providing a potential explanation for the requirement for very high levels of CD154-specific antibodies to prevent allograft rejection.

In addition to the very high levels of CD154-specific antibodies required to prevent allograft rejection, treatment with CD154-specific antibodies (unlike treatment with other antibodies that inhibit T-cell activation) has been associated with thromboembolic complications. Because human platelets release CD154 after activation, and because soluble platelet-derived CD154 activates APCs and endothelial cells in vitro, Xu et al. set out to investigate whether soluble platelet-derived CD154 has a role in allograft rejection. Initial experiments indicated that soluble human recombinant CD154 trimers induced the proliferation of mouse CD154-deficient splenocytes concomitantly stimulated with allogeneic splenocytes (isolated from Balb/c mice) and the production of interleukin-12 (IL-12) by mouse dendritic cells. Further analysis showed that whereas most untreated CD154-deficient mice transplanted with a cardiac allograft had not rejected their allograft 100 days after transplantation, most CD154-deficient mice infused with a single dose of soluble human recombinant CD154 trimers at the time of transplantation rejected their cardiac allograft within 34 days. Similarly, CD154-deficient mice infused with human platelets just before cardiac allograft transplantation rejected their allograft within 40 days unless they were treated with a blocking antibody specific for human CD154, in which case they maintained their allograft for the duration of the experiment (100 days post transplantation). A role for surgical trauma in the activation-induced release of CD154 by the human platelets was indicated by the observation that CD154-deficient mice infused with human platelets 30 days after cardiac allograft transplantation maintained their allograft for the duration of the experiment, whereas CD154-deficient mice infused with soluble human recombinant CD154 trimers at this time point rejected their allograft rapidly.

This study indicates that soluble human CD154 can induce cardiac allograft rejection and that during surgery, activation of human platelets induces the release of this molecule. As the authors point out, this has important implications for the clinical development of CD154-based therapies, as well as providing a potential explanation for the observations that very high levels of CD154-specific antibodies are required to prevent allograft rejection and that treatment with CD154-specific antibodies has been associated with thromboembolic complications.