Regulation of B cell function by the immunosuppressive agent leflunomide

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Leflunomide is an immunosuppressive drug with an unidentified mechanism for suppressing B cell antibody responses.
• The drug inhibits both cellular and humoral immune responses in vivo.

Purpose of the Study:

• To elucidate the mechanism by which leflunomide suppresses B cell antibody production.
• To investigate the direct effects of leflunomide on B cells and their proliferation.

Main Methods:

• In vivo studies assessing T cell-dependent and T cell-independent antigen responses.
• In vitro experiments measuring B cell proliferation and antibody production.
• Cell cycle analysis and Western blot to examine Cdk2 protein levels.
• Uridine rescue experiments to assess pyrimidine synthesis inhibition.

Main Results:

• Leflunomide directly inhibits murine B cell antibody production by decreasing proliferation.
• The drug suppresses both T cell-dependent and T cell-independent responses.
• Leflunomide targets G1 to S and S to G2/M phase transitions, reducing Cdk2 levels.
• Exogenous uridine reverses leflunomide's antiproliferative effect, indicating pyrimidine synthesis inhibition.

Conclusions:

• Leflunomide inhibits B cell proliferation and cell cycle progression by acting as a pyrimidine synthesis inhibitor.
• The drug's mechanism involves direct action on B cells, affecting key cell cycle transition points.
• Understanding this mechanism provides insight into leflunomide's immunosuppressive effects.