Cure of Murine Candidiasis by Recombinant Soluble Interleukin-4 Receptor

Abstract

Neutralization of interleukin (IL)-4 by specific antibody exerts therapeutic activity in a murine model of systemic candidiasis characterized by strong T helper type 2 (Th2) responses. To investigate whether recombinant soluble IL-4 receptor (sIL-4R) could be used to block IL-4 action in vivo, mice treated with pharmacologic doses of sIL-4R at the time of infection were examined for progression of disease, development of footpad responses, serum IgE levels, and cytokine production in vitro by CD4+ lymphocytes. Following sIL-4R treatment, persistent ablation of circulating IL-4 detected by ELISA was associated with a cure rate of > 90% in otherwise lethally infected mice, onset of durable protection, and a shift from a predominant Th2 to a Th1 pattern of reactivity. In addition, when administered to genetically susceptible adult mice with gastrointestinal yeast colonization, the sIL-4R stimulated Th1-associated anticandidal resistance.

Comparison of Pathogenesis and Host Immune Responses toCandida glabrataandCandida albicansin Systemically Infected Immunocompetent Mice

“…Likewise, murine resistance to systemic C. albicans infections was associated with induction of TNF-␣, IL-12, and IFN-␥, while susceptibility to infection was associated with induction of IL-4 and IL-10 (38,61,65,76). Furthermore, mice depleted of endogenous IL-10 (by administration of cytokine-specific neutralizing monoclonal antibody [MAb], receptor antagonists, or IL-10 knockout mice), developed protective immune responses to systemic C. albicans infection, while inhibition of endogenous TNF-␣, IL-12, or IFN-␥ had the opposite effect (9,12,38,40,46,53,63,64,67,78,80).…”

Oral Candidiasis: Clinical Manifestations and Cellular Adaptive Host Responses

“…In contrast, IL_12_deficient mlce were highly susceptible to primary GI infection and showed an elevatid produc_ tion of tL-4 with a concomitant reduction in IFN-1 (Mencacci et al, l99g). Treatment of mice with GI candidiasis by administration of soluble IL-4 receptor (sIL_4R) acceler_ ated clearance of the yeast from the stomach and stimulated Thl-associated resistance (Puccetti et al, 1994).…”

Trends in immunotherapy of fungal infections

“…Neutralization of either of these cytokines by specific monoclonal antibodies augments host resistance, leads to in creased survival of infected mice, and enhances the ability of their macrophages to kill Candida albicans in vitro (19,20). In a different approach, recombinant soluble receptors to IL-4 (sIL-4R) have been cloned (21).The sIL-4R circulate in the bloodstream and are able to bind and neutralize circulating IL-4. Treatment of mice with recombi nant sIL~4R was able to cure potentially lethal subacute disseminated infection caused by Candida albicans (21).…”

“…In a different approach, recombinant soluble receptors to IL-4 (sIL-4R) have been cloned (21).The sIL-4R circulate in the bloodstream and are able to bind and neutralize circulating IL-4. Treatment of mice with recombi nant sIL~4R was able to cure potentially lethal subacute disseminated infection caused by Candida albicans (21).…”