Microbes, immunoregulation, and the gut

Two distinct, but rapidly converging, areas of research ( the hygiene hypothesis and the study of probiotic/prebiotic effects) have emphasised the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. The story began with allergic disorders but now inflammatory bowel disease is increasingly involved

Helminths in the hygiene hypothesis:Sooner or later?

There is increasing recognition that exposures to infectious agents evoke fundamental effects on the development and behaviour of the immune system. Moreover, where infections (especially parasitic infections) have declined, immune responses appear to be increasingly prone to hyperactivity. For example, epidemiological studies of parasite-endemic areas indicate that prenatal or early-life experience of infections can imprint an individual's immunological reactivity. However, the ability of helminths to dampen pathology in established inflammatory diseases implies that they can have therapeutic effects even if the immune system has developed in a low-infection setting. With recent investigations of how parasites are able to modulate host immune pathology at the level of individual parasite molecules and host cell populations, we are now able to dissect the nature of the host–parasite interaction at both the initiation and recall phases of the immune response. Thus the question remains – is the influence of parasites on immunity one that acts primarily in early life, and at initiation of the immune response, or in adulthood and when recall responses occur? In short, parasite immunosuppression – sooner or later

SPONTANEOUS-RECOVERY OF RATS FROM EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IS DEPENDENT ON REGULATION OF THE IMMUNE-SYSTEM BY ENDOGENOUS ADRENAL CORTICOSTEROIDS

Experimental allergic encephalomyelitis (EAE) ' is a paralytic disease that can be induced in a number of animal species by evoking immune responses to antigens in central nervous system (CNS) myelin, and has been studied as a model for multiple sclerosis in man (1). In Lewis rats EAE can be induced either by immunization with guinea pig myelin basic protein (MBP) in CFA (active EAE) or by the intravenous injection into naive syngeneic recipients of spleen cells from animals with active EAE, after in vitro culture of the splenocytes with MBP (passive EAE). The ascending paralysis characteristic of EAE is caused by the action of CD4+ T lymphocytes that produce focal edema in the CNS by increasing vascular permeability (2-4). In both active and passive EAE, animals develop a transient paralysis, and recover completely within 4-5 d of its onset (5). The mechanisms responsible for this spontaneous recovery, which may be similar to the acute remissions occasionally seen in multiple sclerosis, are still poorly understood. Various mechanisms have been proposed, including: suppressor cells (T lymphocytes [6-9], B lymphocytes [10], and macrophages [11]), anti-T lymphocyte idiotype responses (12), serum suppressor factors (13-16), production ofimmunosuppressive factors by filial cells (17-19), regulation by IFN-'Y (20), and neuroendocrine-mediated immunoregulation (21, 22). None of these mechanisms has been shown directly to be necessary for spontaneous recovery from EAE. It has, however, been demonstrated that CD8+ T lymphocytes are not required (23-25). Here we demonstrate that endogenously produced corticosterone plays an essential role in the spontaneous recovery of rats from EAE. Downloaded from jem.rupress.org on February 21, 201

Lessons from helminth infections: ES-62 highlights new interventional approaches in rheumatoid arthritis

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialised countries, this "Hygiene Hypothesis" has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. Here we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine Collagen Induced Arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of IL-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by Th17 and γδ T cells, whilst leaving that of CD49b+ Natural Killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologics, such as "IL-17 blockers", that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential

Immunoregulation in melanoma

IL-10 und TGF-beta sind immunsupprimierende Zytokine, die in verschiedenen Tumoren, u.a. im Melanom, entdeckt wurden und als Hauptursache für das Versagen der Anti-Tumorimmunantwort angesehen werden. Allerdings wurden divergente Daten auch berichtet. Um diese Diskrepanz zu erklären, wurde die Expression dieser Zytokine mittels quantitativer RT-PCR im Melanom und in Haut gesunder Individuen verglichen. Weiterhin wurde die Induktion beider Zytokine in Kokulturexperimenten mit Dendritische Zellen und T-Zellen zusammen mit Tumorzellen sowie ihr Einfluß auf das Immunsystem untersucht. Beide Zytokine sowie deren Rezeptoren wurden im Melanom exprimiert, aber im Vergleich mit gesunder Haut auf signifikant geringerem Level. Dementsprechend waren die Expressionen von IL-10-induzierbare-SOCS-3 und auch TGF-beta-induzierbare-SMAD-7 im Tumor gering und in der gesunden Haut hoch. T-Zellen, die mit einer großen Zahl an Tumorzellen kokultiviert wurden, entwickelten einen anergischen Zustand, aber ohne mit dem IL-10 oder TGF-beta Level zu korrelieren. Dendritische Zellen, die zusammen mit Tumorzellen kokultiviert wurden, wiesen eine gemischte Population an vollständig und unvollständig differenzierten iDCs auf, produzierten hohe Level IL-10 und konnten die CD4 T Zellproliferation weniger effizient induzieren. Trotzdem konnten sie zur Reifung induziert werden, wobei die Blockierung von IL-10 nicht die Fähigkeit der resultierenden, reifen DCs veränderte, CD4 T-Zellproliferation zu induzieren. DCs, deren Reifung in der Gegenwart von Tumorzellen induziert wurde, produzierten erhöhte Level an IL-10, dagegen gleiche oder verminderte Level an TGF-beta und waren effizienter in der Induktion der CD4 T-Zellproliferation. Die fehlende Korrelation von IL-10 und TGF-beta mit den Immundefiziten in situ und in vitro legt den Schluß nahe, ihre Rolle bei Krebs neu zu überdenken.IL-10 and TGF-beta are immunosuppressive cytokines expressed in tumors including melanoma and, therefore, deemed major cause for failing anti-tumor immune responses. To re-evaluate their role, their expression was compared by quantitative RT-PCR in melanoma and skin of healthy individuals, their induction in dendritic cells and T cells co-cultured with tumor cells, and their effects on the immune cells were tested. Both cytokines as well as their receptors were expressed in melanoma at significantly lower levels than in healthy skin. Consequently, the expressions of IL-10-responsive SOCS-3 and TGF-beta-responsive Smad-7 were low in tumors but high in healthy skin. T cells co-cultured with tumor cells developed an anergic state but without increased IL-10 or TGF-beta expression. In vitro tumor-associated iDCs produced high IL-10 levels and were less efficient in inducing T cell proliferation. Nonetheless, they could be induced to mature, and blocking IL-10 did not alter the capacity of the resulting mDCs to induce T cell proliferation. mDCs co-cultured with tumor cells produced increased IL-10 but similar or decreased TGF-beta level and were more efficient in inducing T cell proliferation. The lack of correlation of IL-10 and TGF-beta with immune deficits in situ and in vitro suggests a necessity of re-evaluating their roles in cancer

Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help.

Past work has shown that a subset of effector T cells with unique characteristics could abrogate hapten- or antigen-induced tolerance, and the reconstitution of this immune response has been termed contrasuppression. We have studied contrasuppression in a model of oral tolerance (OT) in which adoptively transferred antigen-specific T contrasuppressor (Tcs) cells reverse OT and result in antibody responses to the eliciting antigen. In the present study, we show that murine intraepithelial lymphocytes (IELs) from mice orally immunized with sheep red blood cells (SRBC) contain T cells that exhibit Tcs cell activity. This effect was mediated by CD3+ gamma/delta T cell receptor-positive (TCR+), but not alpha/beta TCR+ T cells, and gamma/delta TCR+ Tcs cells were associated with both the CD4-,CD8+ and CD4-,CD8- (double-negative) IEL fractions. The CD4-,CD8+ gamma/delta TCR+ IELs were further separated into Vicia villosa-adherent and -nonadherent fractions. Adoptive transfer of V. villosa-adherent gamma/delta TCR+ T cells to mice with OT to SRBC resulted in splenic IgA, IgM, and IgG subclass anti-SRBC responses, while V. villosa-nonadherent gamma/delta TCR+ T cells were without activity. The gamma/delta TCR+ IELs did not support in vitro antibody responses in B cell cultures, while alpha/beta TCR+ IELs were effective T helper cells. Further, cytokine production by the gamma/delta TCR+ IELs was examined, and the gamma/delta TCR+ V. villosa-adherent fraction, which possessed contrasuppressor function, contained low levels of IL-5 mRNA and small numbers of IL-5-producing cells when compared with alpha/beta TCR+ IELs and V. villosa-nonadherent gamma/delta TCR+ IELs. Our results now show that mouse IELs contain two distinct types of T cells that function in the immune response, e.g., alpha/beta TCR+ T cells that produce IL-5 and function as helper cells, and gamma/delta TCR+ T cells that restore antibody responses in mice that had been orally tolerized with antigen

Role and immunomodulatory profile of histamine receptors by H1 and H2 antagonists

The present study was designed to delineate the immunomodulatory role of histamine receptors (H1- and H2-) on induction of antibody response to sheep red blood cells (SRBC), as well as the antibody generation profile, in rabbit system, systemically. The rabbits in two groups received pheniramine (H1-receptor antagonist) and ranitidine (H2-receptor antagonist), respectively, via intramuscular route and were immunized with SRBC intravenously to evaluate suppression or enhancement of antibody responses in sem. A third, control group, received vehicle and were immunized in a similar manner. Histamine released from effector cells (mast cells and basophils) _in vivo_ during inflammatory reactions could influence a detectable antibody response to SRBC as early as day 7-postimmunization (post-I), which lasted until day 28- post-I. Pheniramine-treated rabbits had significantly (*Pa ≤ 0.05 and **Pa ≤ 0.01) more suppressed total serum antibody (IgM + IgG) to SRBC as compared to ranitidine-treated ad cotrol rabbits, while ranitidine-treated rabbits showed different pattern (suppressed or enhanced) during the whole study period. Ranitidine suppressed total antibody level at days 7- and 14- post-I, and enhanced at days 21- and 28- post-I. IgM suppression at day 7- and enhancement at days 14-, 21- and 28- post-I, while IgG suppression during whole study period, as compared to control group was significant (*Pa ≤ 0.05 and **Pa ≤ 0.01) as assessed by direct hemagglutination assay* ad whole SBC-ELISA method**. Here we report that histamine receptor type 2 (H2R)-antagonists have a dominant role on immunosuppression and in immunoregulation of humoral immune responses. Histamine receptor type 2 (H2R)-antagonists are mainly involved in B cell differentiation and proliferation over histamine receptor type 1 (H1R)-antagonists