CD154 as a target for the treatment of thrombotic and inflammatory diseases
Inventors: Denisa Wagner, Prasad Srinivasa, Patrick Andre, Veronica Alves, Lisa Alaimo
Invention Types: Therapeutics
Research Areas: Oncology/Hematology
Keywords: Drug Discovery, Drug ScreeningFor More Information Contact: Ives, Catherine L.
CD154 (also known as CD40L and gp39) is a transmembrane protein in the TNF family, originally identified in CD4+ T lymphocytes and implicated in various immunological functions. Proteolytic cleavage of the CD40L receptor produces the soluble form, sCD40L, which is known to be actively released following platelet stimulation and during acute coronary thrombosis. Building upon work demonstrating CD40L expression in many cells within the vasculature, researchers in Dr. Denisa Wagner’s lab at Boston Children’s Hospital have discovered an expanded role for CD40L in platelets.
In addition to being found on immune cells, CD40L is known to be expressed on activated platelets. Upon interaction with the CD40 receptor, CD40L expressed on platelets is hydrolytically cleaved into its soluble form, which causes it to lose endothelial activating potential. Through binding experiments with recombinant sCD40L, work in the Wagner lab demonstrated that sCD40L binds directly to the aIIbB3 platelet integrin through a KGD motif and that ligand binding induces platelet stimulation and is necessary for the stability of arterial thrombi. Based on this research, compounds that modulate the mobilization of CD40L from platelets, including CD40L antagonists, agents that inhibit hydrolysis or metalloproteinase inhibitors, may provide novel treatments for disorders characterized by inflammation or thrombosis.
Modulation of CD154 regulation represents a promising target for stabilizing the thrombotic process and/or reducing activation of cells involved in the inflammatory response.
CD154 is an important mediator and link between thrombosis and inflammation
Key Publications: Andre et al., 2002. CD40L stabilizes arterial thrombi by a Beta3 integrin-dependent mechanism. Nature Medicine 8(3): 247-252.
US Patent Issued 6,861,504