A Role for IL-1Receptor Antagonist in the Acute Therapeutic Effects of IVIg?.

It has been suggested that IVIg and anti-D may function through the regulation of various cytokines; in particular, significant increases in the anti-inflammatory compound interleukin-1 receptor antagonist (IL-1Ra) have been reported after exposure of patients to IVIg or anti-D. However, the possible role that IL-1Ra may play in the acute therapeutic effects of IVIg or anti-D is unknown. Using a murine model of ITP in which IVIg and anti-RBC-specific antibodies are therapeutically effective, we observed that mice injected with therapeutic doses of IVIg and one anti-RBC antibody (TER-119, which mimics the effects of anti-D) demonstrated increased serum levels of IL-1Ra, reaching peak levels at a time which coincided with an increase in platelet count. Surprisingly, another RBC-specific antibody which also reverses ITP, failed to increase IL-production above basal levels. Thrombocytopenic mice lacking the IL-1 receptor are known to be completely unresponsive to IL-1Ra. These mice responded to both IVIg and TER-119 as successfully as wild-type mice. Injection of mice with as much as 1 mg of recombinant IL-1Ra did not significantly ameliorate thrombocytopenia. To further study the possible indirect role of the IL-1Ra system in the amelioration of murine ITP, we next looked at nitric oxide (NO), an immunoregulatory compound that can be induced by IL-1, stimulate increases in IL-1Ra levels, and has been previously demonstrated to be modulated by IVIg. We report here that treatment of mice with aminoguanidine, an iNOS-selective inhibitor or with L-NAME, a multi-spectrum NOS inhibitor, did not significantly affect the ability of IVIg to ameliorate ITP. These data suggest that while IVIg and TER-119 may mediate the release of IL-1Ra, it is not required for IVIg or anti-RBC antibodies to exert their acute therapeutic effects.