Luis I. Terrazas

Shift from an early protective Th1-type immune response to a late permissive Th2-type response in murine cysticercosis (Taenia crassiceps).

In early stages of experimental murine cysticercosis caused by Taenia crassiceps, there is a clear but transient Th1-type immune response (characterized by high levels of interleukin [IL]-2, interferon-gamma, concanavalin A, and antigen specific response, delayed-type hypersensitivity, and immunoglobulin [Ig]G2a antibodies) that associates with a low rate of parasite reproduction. As time of infection progresses an energic and more permanent Th2-type response follows (characterized by high levels of IL-4, IL-6, IL-10, IgG2b, and IgG1 antibodies) that in turn associates with an increment in the rate of parasite reproduction. The sequential activation of Th1-type and Th2-type responses in murine cysticercosis would appear to favor progressively parasite reproduction, explaining the long time residence and the massive parasite intensity reached in chronic infections.

The Schistosome Oligosaccharide Lacto-N-neotetraose Expands Gr1+ Cells That Secrete Anti-inflammatory Cytokines and Inhibit Proliferation of Naive CD4+ Cells: A Potential Mechanism for Immune Polarization in Helminth Infections

Immunomodulatory oligosaccharides found on helminths also are found in human milk, and both helminths and milk have been shown to be immunosuppressive. We have been examining the immunomodulatory capabilities of two oligosaccharides expressed in milk and on helminth parasites, lacto-N-fucopentaose III and lacto-N-neotetraose (LNnT). In an attempt to dissect mechanisms that lead to Th2 polarization and immune suppression, we examined the early response in mice to the glycoconjugate LNnT-Dextran (LNnT-Dex). We found that injection of LNnT-Dex expanded a cell population, phenotypically defined as Gr1+/CD11b+/F4/80+, as early as 2 h after injection. Examination of spontaneous cytokine production showed that this Gr1+/F4/80+ population of cells spontaneously produced low levels of proinflammatory cytokines, but higher levels of IL-10 and TGF-β ex vivo, compared to peritoneal cells from mice injected with Dex. Gr1+ cells adoptively suppressed naive CD4+ T cell proliferation in vitro in response to anti-CD3/CD28 Ab stimulation. Suppression of naive CD4+ cells involved cell contact and was dependent on IFN-γ and NO, with a discrete role played by IL-10. Coculture of naive CD4+T cells with Gr1+ suppressor cells did not lead to CD4+ T cell apoptosis, although it did imprint on naive CD4+ T cells a response characterized by lower levels of IFN-γ, coincident with increased IL-13 production. Our results suggest that both human milk and helminth parasites may share a ligand-specific mechanism involved in the generation of anti-inflammatory mediators that suppress Th1-type and inflammatory responses.

Chronic Helminth Infection Induces Alternatively Activated Macrophages Expressing High Levels of CCR5 with Low Interleukin-12 Production and Th2-Biasing Ability

ABSTRACT Helminth infections induce Th2-type biased immune responses. Although the mechanisms involved in this phenomenon are not yet clearly defined, antigen-presenting cells (APC) could play an important role in this process. Here, we have used peritoneal macrophages (F4/80+) recruited at different times after challenge with Taenia crassiceps as APC and tested their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of interleukin-12 (IL-12) and nitric oxide (NO), paralleled with low levels of IL-6 and prostaglandin E2 (PGE2) and with the ability to induce strong antigen-specific CD4+ T-cell proliferation in response to nonrelated antigens. In contrast, macrophages from chronic infections produced higher levels of IL-6 and PGE2 and had suppressed production of IL-12 and NO, associated with a poor ability to induce antigen-specific proliferation in CD4+ T cells. Failure to induce proliferation was not due to a deficient expression of accessory molecules, since major histocompatibility complex class II, CD40, and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed. These macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4 but not gamma interferon (IFN-γ), contrary to macrophages from acute infections. Blockade of B7-2 and IL-6 and inhibition of PGE2 failed to restore the proliferative response in CD4+ T cells. Furthermore, studies using STAT6−/− mice revealed that STAT6-mediated signaling was essential for the expansion of these alternatively activated macrophages. These data demonstrate that helminth infections can induce different macrophage populations that have Th2-biasing properties.

The divergent roles of alternatively activated macrophages in helminthic infections

Macrophages play crucial roles in the immune response, as they can initiate, modulate and also be final effector cells during immune responses to infections. Macrophages are derived from myeloid precursor cells in bone marrow and are widely distributed in every tissue of the body. Over the past 10 years, the concepts about macrophage activation have clearly changed; macrophages are not called activated or inactivated as they used to be. These changes in the concept of macrophage response is the result of many in vitro and in vivo studies, but the major support for the current concept of alternatively activated macrophages (AAMφ) comes from parasitic helminth infections. Parasitic helminths have developed complex mechanisms to evade and modulate host immunity. Infections with these parasites induce strong polarized Th2‐type immune responses frequently associated with impaired T‐cell proliferative responses to parasitic or unrelated antigens. Given the recent advances in understanding the immunoregulatory capabilities of helminthic infections, it has been suggested that macrophages can be a target for immunomodulation. Furthermore, they become altered when a host experiences chronic exposure to helminth parasites or their by‐products, which favour the induction of AAMφ. How AAMφ participate in modulating host immunity during helminth infections and what their roles are in clearing or favouring parasite survival remains elusive. Here we review the most recent advances in the literature on AAMφ at the host–parasite interface, including three classes of helminths: nematodes (Brugia, Nippostrongylus, Litomosoides, Heligmosomoides), trematodes (Schistosoma, Fasciola) and cestodes (Taenia, Echinococcus, Hymenolepis).

Th1-type cytokines improve resistance to murine cysticercosis caused by Taenia crassiceps

Abstract Resistance and susceptibility to different parasitic diseases have been associated with the predominance of Th1- or Th2-type immune responses. In experimental murine cysticercosis a Th1 response seems to be involved in resistance, whereas Th2 activity is associated with heavy parasite intensities. To test this notion the roles of Th1- and Th2-type cytokines in infected mice were studied after treatment with anticytokine monoclonal antibodies or with recombinant murine cytokines during early stages of infection. Mice receiving anti-interleukin 10 (IL-10) carried lower parasite intensities than did control mice and developed a strong Th1-type response, whereas mice receiving anti-interferon gamma (IFN-γ) showed a dramatic increase in susceptibility. Treatment with recombinant cytokines confirmed these results; mice receiving IFN-γ and IL-2 showed low parasite numbers, whereas IL-10 induced a significant increase in parasite loads. Thus, the Th1-type immune response plays a fundamental role in protection against Taenia crassiceps cysticercosis, whereas Th2, at least through IL-10, favors parasite establishment.

Macrophage Migration Inhibitory Factor Plays a Critical Role in Mediating Protection against the Helminth Parasite Taenia crassiceps

ABSTRACT To determine the role of endogenous migration inhibitory factor (MIF) in regulation of immune response during murine cysticercosis caused by the helminth parasite Taenia crassiceps, we analyzed the course of T. crassiceps infection in MIF−/− BALB/c mice. MIF−/− mice were highly susceptible to T. crassiceps and developed significantly higher parasite loads compared to similarly infected MIF+/+ mice. Throughout the course of infection, Taenia crassiceps soluble antigen-stimulated spleen cells from both MIF+/+ and MIF−/− mice produced significant and comparable levels of interleukin-4 (IL-4), but those from MIF−/− mice produced significantly more IL-13, as well as gamma interferon (IFN-γ), suggesting that the susceptibility of MIF−/− mice to T. crassiceps was not due to the lack of IFN-γ production. Interestingly, low levels of both total and specific immunoglobulin G2a were observed in MIF−/− cysticercotic mice despite the high IFN-γ levels; in addition, peritoneal macrophages obtained from T. crassiceps-infected MIF−/− mice at different time points failed to respond efficiently to stimulation in vitro with lipopolysaccharide plus IFN-γ and produced significantly lower levels of IL-12, tumor necrosis factor alpha, and NO compared to those from MIF+/+ mice. These findings demonstrate that MIF plays a critical role in mediating protection against T. crassiceps in vivo. Moreover, these findings also suggest that impaired macrophage function rather than the lack of Th1 development may be responsible for mediating susceptibility to T. crassiceps.

Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling

Using STAT6−/− BALB/c mice, we analyzed the role of STAT6-induced Th2 response in determining the outcome of murine cysticercosis caused by the helminth parasite Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response; produced high levels of IgG1, IgE, IL-4, as well as IL-13; and remained susceptible to T. crassiceps. In contrast, similarly infected STAT6−/− mice mounted a strong Th1-like response; produced high levels of IgG2a, IL-12, IFN-γ, as well as nitric oxide; and efficiently controlled T. crassiceps infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to T. crassiceps and, furthermore, that unlike the case in most helminths, immunity against T. crassiceps is mediated by a Th1-like rather than Th2-like response.

Macrophage Migration Inhibitory Factor Contributes to Host Defense against Acute Trypanosoma cruzi Infection

ABSTRACT Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is involved in the host defense against several pathogens. Here we used MIF−/− mice to determine the role of endogenous MIF in the regulation of the host immune response against Trypanosoma cruzi infection. MIF−/− mice displayed high levels of blood and tissue parasitemia, developed severe heart and skeletal muscle immunopathology, and succumbed to T. cruzi infection faster than MIF+/+ mice. The enhanced susceptibility of MIF−/− mice to T. cruzi was associated with reduced levels of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-12 (IL-12), IL-18, gamma interferon (IFN-γ), and IL-1β, in their sera and reduced production of IL-12, IFN-γ, and IL-4 by spleen cells during the early phase of infection. At all time points, antigen-stimulated splenocytes from MIF+/+ and MIF−/− mice produced comparable levels of IL-10. MIF−/− mice also produced significantly less Th1-associated antigen-specific immunoglobulin G2a (IgG2a) throughout the infection, but both groups produced comparable levels of Th2-associated IgG1. Lastly, inflamed hearts from T. cruzi-infected MIF−/− mice expressed increased transcripts for IFN-γ, but fewer for IL-12 p35, IL-12 p40, IL-23, and inducible nitric oxide synthase, compared to MIF+/+ mice. Taken together, our findings show that MIF plays a role in controlling acute T. cruzi infection.

A role for 17-beta-estradiol in immunoendocrine regulation of murine cysticercosis (Taenia crassiceps).

In experimental murine cysticercosis caused by Taenia crassiceps, parasite reproduction is favored by thymectomy or by orchidectomy, and restricted by ovariectomy. Hormonal reconstitution experiments showed that 17-beta-estradiol increases parasite numbers whereas 5-alpha-dihydrotestosterone was ineffective. Parasite numbers decreased with increments in cellular immunity but were insensitive to antibody levels. A possible immunoendocrinological interaction involving estrogen as a depressor of cellular immunity is envisaged in the control of cysticercosis.

IMMUNOLOGICAL MEDIATION OF GONADAL EFFECTS ON EXPERIMENTAL MURINE CYSTICERCOSIS CAUSED BY TAENIA CRASSICEPS METACESTODES

Female BALB/c mice are naturally more susceptible than males to intraperitoneal experimental infection with Taenia crassiceps metacestodes. Gonadectomy tends to equalize susceptibility between sexes by reducing in half the mean individual intensity of females and by tripling that of males. The effect of gonadectomy is seen only in mice with intact immune systems but not in irradiated mice. Purified sex hormones (17-beta estradiol, testosterone, and progesterone) do not affect cysticercus reproduction or growth in vitro. Thus, gonadal effect on mouse susceptibility to cysticercosis appears to be mediated via the immune system, and it is probably not the consequence of the major sex steroids acting directly upon the parasites. Because sublethal irradiation increases the intensity in gonadectomized females and intact males, whereas that of gonadectomized males and intact females remains unchanged, irradiation results are consistent with the hypothesis that immunological events that participate in controlling the growth of cysticerci are inhibited by ovaries and stimulated by testes.