Response: Thrombophilia Associated with Anti-CD154 Monoclonal Antibody Treatment and its Prophylaxis in Nonhuman Primates

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The observations made by Roth and colleagues on FcγRIIA (CD32)-mediated platelet aggregation are interesting and may be relevant to thromboembolic complications caused by CD154 monoclonal antibody (mAb) (1,2). The mechanism they postulate for platelet activation/aggregation resulting from cross linking of the Fc domain of the administrated mAb with FcyRIIA on platelets has provided the impetus for ongoing efforts to develop a truncated IgG molecule, which retains the remarkable efficacy of the anti-CD154 reagent while avoiding thrombophilia. We are also intrigued by a recent report by Henn et al. on coexpression of CD40 and CD154 on platelets (3). They found that CD40 is constitutively expressed on resting platelets, and interaction with CD154 on activated platelets induces rapid downregulation of membrane-bound CD154 and cleaves it to biologically inactive soluble CD154 (sCD154). The authors concluded that cleavage of CD154 from the surface of activated platelets is a central mechanism limiting the inflammatory action of CD154 in the vascular system. Interestingly, the release of sCD154 was abrogated in the presence of anti-CD40 mAb. It is possible that anti-CD154 mAb also can abrogate downregulation of CD154 on platelets leading to unlimited platelet activation in vivo. We anticipate that further such findings and those reported by Roth et al. (2) will lead a better understanding of the CD40-CD154 platelet interactions and delineate effective means to prevent the thromboembolic complications that have been encountered in the initial anti-CD154 mAb therapy trials. Tatsuo Kawai A. Benedict Cosimi Harvard Medical School, Massachusetts General Hospital, Boston, MA