In Vitro Analysis of the Mode of Inhibition of T-Cell Proliferation by Leflunomide, A Novel Immunomodulatory Agent
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Authors
Hamzavi, Fasahat H.
Issue Date
1993
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Leflunomide (HW A 486) is a novel immunosuppressive drug that has
shown promising results in preventing graft rejection and curing some
autoimmune diseases in rats. The mechanism by which HWA 486 inhibits T-cell
proliferation has not yet been characterized. This study utilized the
human interleukin-2 (IL-2) dependent leukemia T-cell line, Kit 225 (Hori et
al., 1987), to determine at which point of the signal transduction pathway of
T-cell proliferation HWA 486 is taking its effect. Results of [3H] thymidine
experiments demonstrated that HW A 486 was unable to inhibit proliferation
of Kit 225 cells. The ineffectiveness of HW A 486 to inhibit proliferation of Kit
225 cells was unexpected, but subsequent research on this cell line (Sawami et
al., 1992) indicated that the Kit 225 cell line does not express lck tyrosine
kinase activity. Lck is a protein bound to the cytoplasmic end of the
interleukin-2 receptor (IL-2R) and is thought to be necessary in the signal
transduction pathway of T-cell proliferation (Horak et al., 1991). The effect of
HW A 486 on general tyrosine kinase activity was then assessed by
immunoblotting analysis of phosphotyrosine kinase activity of Kit 225 cells.
Immunoblotting indicated that HWA 486 was ineffective in inhibiting the
other tyrosine kinase activity involved in Kit 225 cells. On the other hand,
genistein, a general tyrosine kinase inhibitor, was able to slightly inhibit this
kinase activity. Since HWA 486 was ineffective in inhibiting the general
tyrosine kinase activity within the lck deficient Kit 225 cells, it was possible to
assume that HW A 486 was specific for lck tyrosine kinase activity. It is
therefore possible to deduce that a hypothetical mechanism by which HWA
486 takes its effect is to inhibit lck tyrosine kinase activity of the IL-2R which
in turn inhibits T-cell proliferation.
Description
v, 24 p.
Citation
Publisher
Kalamazoo College
License
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