Most inbred strains of mouse infected with the intestinal nematode Trichuris muris are resistant to infection expelling the parasite before adult worms establish. However, a few susceptible strains exist that are incapable of worm expulsion and harbor chronic infections of mature adult worms. Analyses of in vitro cytokine production by cells from the draining lymph node (mesenteric lymph node) have indicated that expulsion phenotype is tightly correlated with the selective expansion of helper T cells (Th) of the Th1 or Th2 cell subset within the mesenteric lymph node, resulting in susceptibility and resistance to T. muris, respectively. We have now confirmed and extended our in vitro observations in a series of experiments involving the in vivo manipulation of host cytokine levels. Depletion of interferon (IFN)-gamma in normally susceptible mice resulted in expulsion of the parasite, representing the first evidence for a role for IFN-gamma in the establishment of chronic helminth infection. Blocking interleukin (IL)-4 function in normally resistant animals prevented the generation of a protective immune response allowing adult stages of the parasite to develop. Conversely the administration of IL-4 to a normally susceptible host facilitated expulsion and indeed enabled established adult worms to be expelled when administered late in infection. In all cases assessment of a variety of in vivo parameters indicative of a Th1- or Th2-type response (parasite-specific immunoglobulin (Ig) G2a and the parasite-specific IgG1, total IgE levels and intestinal mastocytosis, respectively) demonstrated that the in vivo modulation of a Th1- or Th2-specific cytokine allowed the reciprocal Th cell subset to expand and become dominant with dramatic consequences for worm expulsion.

Parasitic helminths typically induce components of immediate-type hypersensitivity, including elevated serum IgE, eosinophilia, and mucosal mast cells. These responses are T-cell-dependent and associated with rapid expulsion of parasitic worms from a sensitized host; existing experimental systems have failed to derme the precise role of cytokines in these responses. We report here that antiinterleukin 4 or anti-interleukin 4 receptor antibodies block the polyclonal IgE response to a parasitic nematode, Heligmosomoides polygyrus, and abrogate protective immunity to the infection. In contrast, anti-interleukin 5 antibody prevented H. polygyrus-induced eosinophilia but did not prevent protection. These data provide evidence that a specific cytokine affects the physiology and survival of a parasitic nematode in the host.

SummaryAmong other effects, prostaglandins (PG) of the E series are known to inhibit several acute and chronic inflammatory conditions in vivo and proinflammatory cytokine production by activated macrophages in culture. The research presented here demonstrates that the inhibitory effect of PGE2 on tumor necrosis factor oe (TNF-oL) and interleukin 6 (IL-6) production by lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages involves IL-10. In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-ol and IL-6, but not of lactate or nitric oxide. The decrease in the level of these cytokines is inversely proportional to the increase in immunoreactive IL-10. This differential inhibitory effect of PGE2 is mimicked by agents that elevate intracellular levels of cAMP, but not cGMP. Neutralizing anti IL-10 antibody but not neutralizing antibodies against other macrophage secretory products (IL-6, leukemia inhibitory factor, and transforming growth factor fl [TGF-fl]), significantly reverse the potent inhibitory effect of PGE2. In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-cr and IL-6 levels. Anti-IL-10 antibody substantially enhanced the LPS-induced TNF-o~ and IL-6 levels in mice that received either LPS alone or LPS plus PGE2. These results suggest that the antiinflammatory effect of PGE2 on mononuclear phagocytes is mediated in part by an autocrine feedback mechanism involving IL-10.M ononuclear phagocytes (macrophages) play a central role in the regulation of immune responses as well as in both acute and chronic inflammation. The mechanisms that participate in these activities are believed to be multifactorial and involve macrophage secretory products (for a review see reference 1). TNF-ol is an important macrophage inflammatory cytokine that mediates a wide range of biologic functions. TNF-c~ is believed to play a major role in septic shock, and to contribute to the pathogenesis of AIDS and several inflammatory and autoimmune diseases (for reviews see references 2, 3). Recently, a number of regulatory factors were described as having the capacity to block macrophage functions, including TNF-cr release. These molecules, also termed "macrophage-deactivating factors;' include PG of the E series (4-8), TGF-3 (9), IL-4 (10), and 12). In addition to their capacity to induce pain, vascular changes and downregulation of T cell functions, PG have been shown to exhibit antiinflammatory properties on macrophages. For example, stimulation of macrophages by LPS or by TNF-c~ induces PGE2 production (13,14), and the addition of PGE2 to LPS-stimulated cells inhibits TNF-c~ mRNA expression and protein secretion (6-8). This information leads to the hypothesis that the release of PG during LPS-induced inflammation constitutes a negative-feedback mechanism that limits the magnitude of inflammatory cytokine production. In vivo, the exogenous administration of PGE suppresses adjuvant arthritis in rats (15), inhibits the manifestation of interstitial nephritis (16), and...

IL-4/B cell stimulatory factor-1 is a T cell-derived lymphokine that has been shown to enhance IgG1 and IgE and to suppress IgG3 and IgG2b secretion by B cells stimulated with bacterial LPS. We show here that the stimulation of IgG1 and IgE secretion in response to rIL-4 is differentially regulated. The dose-response curve for IgG1 production is bimodal with peaks at 100 and 10,000 U/ml. IgE production is modest at 100 U/ml and exhibits a progressive enhancement as the IL-4 concentration is increased to 10,000 U/ml, reaching approximately 1 microgram of IgE from an initial cell number of 2 X 10(4). Both of these effects are reversed by monoclonal anti-IL-4 antibody. Neither the enhancing nor suppressing effects of IL-4 can be explained by changes in viable cell yields or [3H]thymidine incorporation. The production of both IgG1 and IgE is controlled by IL-4 in a two-phase manner. During the initial 2 d of culture with LPS, IL-4 action for both IgG1 and IgE production is relatively concentration independent at doses greater than 600 U/ml. This 2-d treatment leads to maximal IgG1 production at day 6 with no further addition of IL-4. Addition of IL-4 during the final 4 d of culture has no effect at concentrations under 100 U/ml. At higher concentrations, IL-4 is strikingly suppressive for IgG1 production. By contrast, little IgE is produced unless IL-4 is present after 2 d of culture and the response is directly dependent on the concentration of IL-4 during this second phase of culture with maximal responses observed at 10,000 U/ml. These differences in IL-4 requirements for IgG1 and IgE production, respectively, may have an important role in the regulation of the synthesis of these isotypes in responses to microbial antigens.

The lymphokine B-cell stimulatory factor 1 (BSF-1) has been shown to greatly enhance the differentiation of lipopolysaccharide-activated B cells into IgGl-and IgEsecreting cells in vitro. To determine whether in vivo IgG1 and IgE antibody responses are BSF-1 dependent, the ability of a monoclonal rat IgG1 anti-BSF-1 antibody, 11B11, to affect polyclonal IgG1 and IgE production in mice infected with the nematode parasite Nippostrongylus brasiliensis or iIiected with a purified goat antibody to mouse IgD was studied. 11B11-containing ascites fluid or purified 11B11 strongly inhibited IgE production in both systems but did not affect IgG1 production, while control ascites or normal rat IgG1 had no IgE-inhibitory activity. These results indicate an important physiologic role for BSF-1 in the generation of IgE antibody responses and suggest means for limiting the production of antibodies responsible for allergic reactions without inhibiting protective antibody responses.IgE has a crucial role in the pathogenesis of allergic reactions (1, 2), is thought to be important for host elimination of helminthic parasites (3-5), and is produced in relatively large quantities by animals infected with these parasites (6)(7)(8)(9). The generation of IgE-secreting cells has been shown to be dependent upon helper T lymphocytes (10); no IgE secretion is seen in parasite-infected congenitally athymic (nude) mice (11, 12) or parasite-infected mice injected with a monoclonal antibody (anti-L3T4) (13) that blocks helper T-cell function (14). The nature of the T-cell help required for the generation of an IgE response in vivo is not certain, but soluble, T-cell-produced, IgE binding factors have been shown to modulate in vitro generated IgE responses (15). The demonstration that a purified murine T-cell lymphokine, B-cell stimulatory factor 1 (BSF-1)1 (17,18), is capable of inducing a greater than 100-fold increase in IgE secretion in vitro by lipopolysaccharide-activated mouse splenic B-cell blasts (19), suggested that this lymphokine might be important in the in vivo stimulation of IgE secretion. This led us to study whether a monoclonal anti-BSF-1 antibody was capable of inhibiting a mouse polyclonal IgE response to infection with the nematode parasite Nippostrongylus brasiliensis (Nb) or to injection of an affinity-purified goat anti-IgD (GaM8). Results of these studies indicate that anti-BSF-1 antibody substantially inhibits IgE but not IgG1 secretion in these mice and thus strongly suggest a specific and important role for BSF-1 in the physiologic stimulation of IgE responses.MATERIALS AND METHODS Animals. Female BALB/c and male athymic nude mice were obtained from the National Institutes of Health Small Animals Division (Bethesda, MD) and were used at 8-12 weeks of age.Antibodies. Affinity-purified GaM8 (20), rabbit antibody specific for the e chain of mouse IgE (RaME) (9), and alkaline phosphatase conjugated to affinity-purified, mouse serumabsorbed, goat anti-rabbit immunoglobulin (21) were prepared. The rat-mouse hybri...