Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154.
CD154 is a cell surface molecule expressed on activated T cells that binds to CD40, an activating molecule on APCs. Its blockade has been shown to prevent allograft rejection, presumably by interrupting interactions between T cells and APCs. It is known that activated human platelets express and shed CD154 and can induce APC activation and other immune processes in vitro. Here we show that platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of any cellular source of this molecule. CD154-KO mice reject cardiac allografts after receiving CD154-expressing human platelets or recombinant CD154 (rCD154) trimers. Treatment with the human CD154-specific mAb 5c8 specifically prevents this induced rejection. Soluble trimers, but not platelets, induce rejection when infused temporally remote from the surgical procedure, suggesting that surgically induced platelet activation is required for CD154 release. Allograft rejection can thus be instigated by activated platelets through CD154. These data implicate platelets as a proximal component of acquired alloimmunity, providing insight into the mechanisms of allograft rejection and the physiological response to trauma in general.
Transplantation Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, United States Department of Health and Human Services, Bethesda, Maryland 20892, USA.
He
H
Xu
Xiaojie
X
Zhang
Roslyn B
RB
Mannon
Allan D
AD
Kirk
D000818:Animals; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood* / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D006084:Graft Rejection / Q000097:blood* / Q000503:physiopathology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation; D017713:Platelet Transfusion; D011485:Protein Binding; D012995:Solubility; D014184:Transplantation, Homologous
D023201:CD40 Ligand