The relative contributions of local T helper cell type 1 (Th1)- and Th2-like responses to the course of primary and secondary gastrointestinal (GI) candidiasis were examined in adult immunocompetent BALB/c mice. Both Th1 cytokines, such as interferon-gamma (IFN-gamma), and the Th2 cytokines, interleukin (IL)-4 and IL-5, were produced by CD4+ cells from Peyer's patches (PP) and mesenteric lymph nodes at a time when the fungus was cleared from the stomach and intestine. Augmentation of antigen-specific Th2-like responses by treatment with cholera toxin did not modify the course of disease. In contrast, treatment with soluble IL-4 receptor, which increased Th1 cells, was associated with enhanced yeast clearance. In addition, IFN-gamma but not IL-4 mRNA was present in PP and spleen CD4+ cells in mice resistant to subsequent GI inoculation. Activation of Th1- but not Th2-like responses may be responsible locally for controlling GI candidiasis and generating protective immunity.

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.

The immune response against Leishmania donovani infection has been investigated in one resistant mouse strain (C3H/HeJ) and three susceptible mouse strains (C57BL/6, BALB/c, and B10D2/n). In order to correlate the strain-specific course of infection with the individual T cell response phenotype, the ex vivo cytokine secretion patterns of splenic lymphocytes were assessed by ELISA (interferon-y [IFN-gamma], interleukin-4 [IL-4], IL-10) or by bioassay (IL-2). The strain-dependent differences in the course of infection correlated closely with the potency of T cells to produce IFN-gamma. C3H/HeJ mice produced high amounts of IFN-gamma before and during infection, whereas susceptible mice produced low amounts of IFN-gamma early during L. donovani infection. However, C57BL/6 mice, which recovered from the infection rapidly after the acute stage, developed marked IFN-gamma response within the first 30 days of infection. In contrast, in BALB/c and B10D2/n mice, the IFN-gamma production diminished during the acute stage, and this was associated with a delay in recovery and with subsequent switching into the chronic stage. Interestingly, CD8+ T cells contributed significantly to IFN-gamma production during this phase. In contrast to IFN-y, the levels of IL-4 in response to antigen or mitogen ex vivo were always very low. Moreover, neutralization of endogenous IL-4 in vivo by treatment with soluble murine IL-4 receptor did not result in significant decreases in the parasite burdens in spleen and liver but did cause a decrease in the serum IgE level of L. donovani-infected BALB/c mice. These results confirm that in visceral leishmaniasis a Thl-dominated immune response is protective against the L. donovani parasites and, furthermore, that the capacity to produce IFN-gamma rather than the presence of IL-4 determines the efficacy of the immune response in susceptible mice. The data show that CD8+ T cells represent an important source of IFN-gamma during L. donovani infection in susceptible mice, implying a role for this cell type in healing and development of protective immunity.

In this study, the effect of soluble IL-4 receptors (sIL-4R) on murine allergen-induced IgE and IgG1 production was examined. Lymphocytes from mice sensitized to the allergens ragweed (RW) or ovalbumin (OVA) in vivo were restimulated in vitro with the sensitizing allergen in the presence of either a soluble murine sIL-4R, a dimeric sIL-4R Ig fusion protein (sIL-4R/Fc), or anti-IL-4 antibody in 14-day cultures. Both monomeric and dimeric SIL-4R inhibited polyclonal IgE (∼70%) and IgG1 (∼35%) production in a dose-dependent fashion, similar to that observed in the presence of the anti-IL-4 antibody. Allergen-specific IgE and IgG1 were inhibited to a greater degree. Addition of sIL-4R was most effective when present in the culture during the first 3 days and added not later than day 6. In kinetic experiments, we distinguished ongoing IgE production from precommitted B cells versus newly induced IgE synthesis and found that newly induced IgE production was the major target of the sIL-4Rs. These data demonstrate the efficacy of sIL-4R in inhibiting the early stages of the IgE B-cell maturation pathway and indicate the potential of sIL-4R for the inhibition of IgE production in vivo.

The effects of local versus systemic treatment with soluble IL-4 receptors (sIL-4R) were tested in a model of allergen-induced immediate hypersensitivity responses in BALB/c mice. Mice sensitized through the airways to ovalbumin (OVA) by ultrasonic nebulization once a week for 4 weeks developed increased serum anti-OVA IgE and IgG1 antibody titers and these were accompanied by immediate-type skin test responses to the allergen. These responses were also associated with the development of increased airway responsiveness (AR) as monitored by electrical field stimulation of tracheal smooth muscle preparations in vitro. Sensitized mice, treated by intraperitoneal injections of sIL-4R (150 μg/ injection) administered in parallel to the sensitization protocol, developed significant suppression of anti-OVA IgE, anti-OVA IgG1 antibody production and of immediate cutaneous hypersensitivity responses. Airway responsiveness was normalized to some extent. Total IgE production was only slightly reduced. These effects were comparable to the findings following intraperitoneal injection of monoclonal anti-IL-4 antibody. Administration of sIL-4R via the airways was also effective in inhibiting the development of immediate hypersensitivity responses, including IgE production, and was more potent in normalizing airway responsiveness. These effects were achieved at lower concentrations than needed for systemic treatment. These data suggest that delivery of sIL-4R via the airways can effectively modulate the development of immediate hypersensitivity and airway hyperresponsiveness in response to aerosolized allergen.