How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis

Richard Glynne, Srinivas Akkaraju, James I. Healy, Jane Rayner, Christopher C. Goodnow () and David H. Mack
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Richard Glynne: Stanford University
Srinivas Akkaraju: Stanford University
James I. Healy: Stanford University
Jane Rayner: Medical Genome Centre, John Curtin School of Medical Research, Australian National University
Christopher C. Goodnow: Stanford University
David H. Mack: Eos Biotechnology

Nature, 2000, vol. 403, issue 6770, 672-676

Abstract: Abstract 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, NFκB and JNK), through inhibition of calcineurin1, and inhibit mature lymphocyte proliferation to antigen2,3,4. 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 tolerance5. 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.

Date: 2000
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DOI: 10.1038/35001102

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