IL-18 Binding Protein Protects Against Contact Hypersensitivity

Abstract

Allergic contact dermatitis, the clinical manifestation of contact hypersensitivity, is one of the most common disorders of the skin. It is elicited upon multiple cutaneous re-exposure of sensitized individuals to the sensitizing agent. In this study, we demonstrate that using IL-18 binding protein (IL-18BP) to neutralize IL-18 significantly reduced clinical symptoms in a murine model of contact hypersensitivity. Furthermore, IL-18BP alleviated the relapses during established disease, as indicated by significant protection during re-exposure of mice that had previously undergone a contact hypersensitivity response without treatment. Although edema was not influenced, IL-18BP reduced the number of T cells homing to sites of inflammation, resulting in diminished local production of IFN-γ. Thus, by preventing the accumulation of effector T cells to the target tissue, IL-18BP appears to be a potent protective mediator to counter skin inflammation during contact hypersensitivity. Taken together with the evidence that IL-18 is present in tissue samples of the human disease, our data reinforces IL-18BP as a candidate for this therapeutic indication.

Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

“…The disease-limiting action of AdIL-18bp was a robust finding that was reproduced in EAE induced by two different encephalitogens in two strains of mice, and was observed in two separate animal facilities. IL-18bp has beneficial effects in a variety of model system of inflammatory disease, including contact hypersensitivity (20), diabetes (21), and models of inflammation-induced liver disease (18,19). In the CNS, IL-18bp was shown to have a beneficial effect on recovery from closed head trauma (22), and MBPspecific Th2 cell lines engineered to express IL-18bp had a beneficial effect on EAE (44).…”

“…It has been shown that IL-18bp can inhibit IL-18R signaling via an IL-18-independent interaction with IL-18Rb subunit (17). Several studies have demonstrated that administration of exogenous IL-18bp can have a therapeutic effect in a variety of inflammatory diseases (18)(19)(20)(21), and IL-18bp improved recovery in a model of closed head trauma (22), although there is a paucity of studies on the role of IL-18bp in the CNS.…”

IL-18 Contributes to Renal Damage after Ischemia-Reperfusion

“…Macrophage accumulation in association with increased IL-18 expression has been described in a number of other inflammatory and immune-mediated processes, including biliary atresia, 39 contact hypersensitivity, 40 and lupus-like autoimmune syndrome. 27,28 Of particular interest, in the setting of rheumatoid arthritis, increased production of IL-18 associated with these inflammatory processes is principally from macrophages.…”

Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein

“…Orthopoxvirus IL-18BP contributes to virulence by downmodulating IL-18-mediated immune responses (5,9). The mechanism by which IL-18BP inactivates hIL-18 is unclear, but its potent ability to inhibit hIL-18 has prompted an interest in developing IL-18BP as therapeutics (10,11) because aberrant expression of IL-18 is associated with severe inflammatory conditions, such as some autoimmune diseases. Recombinant human IL-18BP has been shown to be effective at treating inflammatory skin diseases and LPS-induced liver injury (10,11).…”