The Novel Immunosuppressant FK778 Inhibits Formation of the Immunologic Synapse

• Published in: Transplantation proceedings Vol. 37; no. 4; pp. 1970 - 1971
• Main Authors: Zeyda, M., Geyeregger, R., Poglitsch, M., Watschinger, B., Hörl, W.H., Stulnig, T.M., Säemann, M.D.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-05-2005; Elsevier Science
• Subjects: Alkynes; Biological and medical sciences; Cell Communication - drug effects; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunosuppressive Agents - pharmacology; Isoxazoles - pharmacology; Lymphocyte Activation - drug effects; Medical sciences; Nitriles; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tissue, organ and graft immunology; Medicine; Synapse; Treatment; Surgery; Graft; Inhibitor; Transplantation; Immunosuppressive agent
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2005.03.083

The malononitrilamide FK778 is a derivative of A77 1726, the active metabolite of the antirheumatic drug leflunomide. A77 1726 inhibits de novo pyrimidine synthesis and activity of Src-family kinases; thus, it may interfere with T-cell proliferation as well as with early T-cell signaling. Formation of a stable interaction between T cells and antigen-presenting cells (APC)—the immunologic synapse—has emerged to be of crucial importance for T-cell activation. Here in we show that FK778 inhibits formation of the immunologic synapse by blocking superantigen-stimulated relocalization of adhesion (LFA-1), and signaling molecules (CD3) to the T-cell/APC contact site. These data show that FK778 affects T-cell/APC interactions, particularly events crucial for T-cell adhesion and formation of stable conjugates underlying sustained and effective T-cell activation. Thus, in this model system close to physiologic T-cell stimulation, FK778 affects critical events in the course of T-cell-mediated immune responses earlier than T-cell proliferation, which may contribute to its immunosuppressive potential.