How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis.
Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NFkappaB and JNK), through inhibition of calcineurin, and inhibit mature lymphocyte proliferation to antigen. Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance. Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.
Glynne
R
R
Department of Microbiology and Immunology, Beckman Center, Stanford University, California 94305, USA.
Akkaraju
S
S
Healy
J I
JI
Rayner
J
J
Goodnow
C C
CC
Mack
D H
DH
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009113:Muramidase / Q000276:immunology; D017634:Self Tolerance; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D020928:Mitogen-Activated Protein Kinases; D009113:Muramidase; D016559:Tacrolimus