Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine.
BACKGROUND
Leflunomide is an isoxazol derivative with immunosuppressive capacities in various experimental allo- and xenotransplantation models. Two main mechanisms of action have been described: Inhibition of pyrimidine de novo synthesis and impairment of tyrosine phosphorylation of different tyrosine kinases involved in receptor signaling via B cell and cytokine receptors.


METHODS
Interference of Leflunomide with the IgM antibody responses to vesicular stomatitis virus (VSV, T-independent type 1), IgM to recombinant VSV glycoprotein (T-independent type 2), and IgG to lymphocytic choriomeningitis virus (LCMV, T-dependent) were analyzed whereas the cytotoxic T cell (CTL) response was examined after LCMV infection. Interference with the CD8+ T cell-mediated autoimmune diabetes in a transgenic mouse expressing the LCMV-glycoprotein in the pancreatic islets was studied as a model for T cell-mediated autoimmune diseases. Uridine substitution experiments were performed to differentiate between the above mentioned two mechanisms of action on different functions of the immune system in vivo.


RESULTS
Leflunomide at 35 mg/kg/day suppressed the humoral immune response against all antigens tested. Similar effects on T-independent compared to T-dependent antibody responses required two to four times higher drug doses. CTL responses to LCMV were considerably impaired. Uridine substitution prevented lethal VSV encephalitis under Leflunomide treatment by restoring the neutralizing IgM and IgG responses. However, the inhibition of LCMV specific CTLs and suppression of CD8+ T cell-mediated autoimmune diabetes remained unaffected by additional uridine treatment.


CONCLUSIONS
Leflunomide-mediated suppression of B cell and T helper cell activity but not of CTLs largely depends on inhibition of pyrimidine de novo synthesis.
Pinschewer
D D
DD
Institute of Experimental Immunology, Department of Pathology, University Hospital Zurich, Switzerland.
Ochsenbein
A F
AF
Fehr
T
T
Zinkernagel
R M
RM
D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis*; D000917:Antibody Formation / Q000187:drug effects; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology; D014529:Uridine / Q000494:pharmacology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D000914:Antibodies, Viral; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide; D014529:Uridine