The novel immunosuppressant FK778 inhibits formation of the immunologic Synapse.
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.
Zeyda
M
M
Clinical Division of Nephrology and Dialysis, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria.
Geyeregger
R
R
Poglitsch
M
M
Watschinger
B
B
Hörl
W H
WH
Stulnig
T M
TM
Säemann
M D
MD
D000480:Alkynes; D002450:Cell Communication / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009570:Nitriles; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide