ANTI-CYTOKINE AUTOANTIBODIES - EPIPHENOMENON OR CRITICAL MODULATORS OF CYTOKINE ACTION

Low amounts of high-affinity autoantibodies to various cytokines have been detected in sera from healthy donors. Their levels, although high ly variable, are increased in the circulation of patients subjected to cytokine therapy or suffering from a variety of immunoinflammatory di seases. It has been suggested that these autoantibodies play a regulat ory role in the intensity and duration of an immune response. The anti bodies may prevent the binding of a cytokine to its specific cell surf ace receptor thereby neutralizing its biological activity in vivo. The y may also act as carrier proteins preventing the rapid elimination of a cytokine from the circulation and thus increase its bioactivity. Ad ditionally or alternatively, autoantibodies may modulate cytokine-indu ced intracellular signal transduction pathways or trigger complement-m ediated cytotoxicity towards cells carrying membrane-bound cytokines. The autoantibodies may exert their regulatory role in compliance with other factors that control cytokine activity, including soluble cytoki ne receptors, cell surface decoy receptors, and receptor antagonists. Although not favored by many investigators, a less sophisticated role for naturally occurring anti-cytokine autoantibodies should be conside red as well. Recent evidence has shown that autoantibodies are generat ed at a high frequency as part of a response to foreign antigens. Thes e antibodies are produced by B cells arising from the process of somat ic mutation. Thus anti-cytokine autoantibodies may be the result of a ''leaky'' B cell response triggered by immunoinflammatory processes. H igh-titered autoantibodies induced by cytokine therapy are of clinical concern since their occurrence is often associated with the loss of r esponse to treatment. Moreover, they may also neutralize endogenously produced cytokines with possible pathological consequences. In this pa per we have reviewed the available information on the biological and c linical significance of both naturally occurring and therapeutically i nduced anti-cytokine autoantibodies in animals and man with the emphas is on antibodies directed to interferons.