Modulation of the immune response by the cholera-like enterotoxins

Cholera toxins and heat labile enterotoxin from E. coli differ from most soluble proteins in eliciting systemic immunity both against themselves and unrelated admixed antigens, rather than tolerance following administration to a mucosal surface. Several reports have also demonstrated preferential induction of Th2-type responses when these molecules are used as adjuvants. Conversely, these proteins and their non-toxic derivatives, including the B sub-units are also able prevent and alleviate autoimmune diseases in na?ve and systemically immune hosts demonstrating wide-ranging effects on the immune system. The recent observation that amelioration of autoimmune disease is associated with the generation of regulatory T cells which inhibit pathogenic Th1 responses may also help to consolidate these two apparently contradictory outcomes of exposure to the cholera-like enterotoxins. Furthermore, the observation that EtxB is able to alleviate autoimmune disease in the absence of conjugation to autoantigen highlights its potential for use in the clinical setting where the target antigen is often unknown. Direct effects on T cells, B cells and APC have been demonstrated in vitro which have provided insights into how these molecules may elicit these diverse effects. Further investigation is required for elucidation of the mechanisms of action of adjuvanticity and tolerance induction by these molecules to realise their potential for use in vaccines and therapies for autoimmune disease in humans.     

Modulation of the adoptive immune response in mice by histamine

The immunomodulatory actions of histamine in mice were examined by a combined in vitro/in vivo approach. Spleen cells from mice were incubated between 2 and 24 hours with histamine (10(-12)-10(-3) M) under conditions which prevent a change of the free histamine concentration. The cells were subsequently transferred to sublethally irradiated syngenic mice in order to measure the adoptive IgM response. Only stimulatory effects of histamine were found at NMRI mice. However, both stimulatory and inhibitory actions were observed at different histamine concentrations if mice of the strains AB or XVII were used. The graft versus host reaction was measured after transfer of histamine treated spleen cells (strain XVII) to neonatal F1 (XVII X B10.LP) hybrid mice and revealed both suppressive and stimulatory effects of histamine at different concentrations. A maximal expression of the immunomodulatory effects of histamine was found after 8 hours of preincubation with the donor cells. The action of selective histamine antagonists and cell separation experiments indicated that the effect of histamine on the adoptive IgM response was mediated by H2-receptors on spleen T-cells. Summarizing, the results indicate that low histamine concentrations elicit bidirectional immunomodulatory effects in mice which vary considerably among different strains.     

Modulation of the immune response to Listeria monocytogenes by benzene inhalation

Benzene is a potent bone marrow toxicant. While all blood cell types are targets for benzene poisoning, lymphocytes are particularly sensitive. The immunotoxic consequences of benzene or its metabolites have been demonstrated in a number of in vitro studies; however, little data exist regarding the effects of benzene on host resistance to infectious agents. This investigation examined the effects of benzene on murine resistance to an infectious agent, Listeria monocytogenes. Four concentrations of benzene were employed, 10, 30, 100, and 300 ppm. To determine recovery from the effects of benzene, two exposure regimens were employed: 5 days prior to infection (preexposure), or 5 days prior to and 7 days during infection (continuous exposure). Appropriate air controls were maintained. Splenic bacterial counts and immune responsive cell populations were determined from mice killed at Days 1, 4, and 7 of infection. Preexposure to benzene produced increased bacterial numbers at Day 4 of the infection only at the highest benzene concentration (300 ppm). In contrast, continuous exposure produced increased bacterial numbers at Day 4 of infection at all but the lowest benzene concentration (10 ppm). Bacteria counts were not increased in any benzene-treated group at Day 1 or Day 7 of infection. The increased bacterial numbers at Day 4 suggest an effect on cell-mediated immune responses. Both T and B lymphocytes were particularly sensitive to benzene exhibiting reductions at all concentrations greater than or equal to 30 ppm for both exposure regimens. Esterase-positive cells, however, were relatively resistant to benzenes effects. The results point to a benzene-induced delay in the immune response to L. monocytogenes.     

Modulation of murine in vitro immune response by verapamil (V)

Functionally distinct lymphocyte subsets differ with regard to necessary activation signals. In selected circumstances lymphocyte activation has been shown to be critically dependent upon transcellular calcium influx. Whether calcium plays a central role in the activation of all lymphocytes remains to be determined. The effect of the calcium channel blocker verapamil on the induction of murine cytotoxic T lymphocytes (CTL), suppressor cells, T helper cells, and B cells was investigated. Verapamil (V) was found to inhibit the induction of cytotoxic effector cells. V acted primarily on the afferent limb of this immune response, was synergistic with cyclosporin A (CsA), and its effects could be largely reversed by the addition of exogenous helper factors. V also inhibited B cell proliferation in response to anti-mouse IgM in the presence of 2-mercaptoethanol, but in the absence of cognate or non-cognate T cell help. In contrast to this, V did not inhibit the activation of cells capable of inducing B cell proliferation nor did it inhibit the induction of suppressor cells. The selective suppression of V is discussed in terms of activation requirements of CTL, suppressor cells and helper cell subsets.     

Modulation of immune responses in mice by d-limonene

The immunotoxicologic effects of d-limonene were determined. This naturally occurring substance is widely used in food flavorings and is a common additive in cosmetics. In the present study, BALB/c mice were treated with d-limonene for 9 wk. Effects on T- and B-cell responses were determined after 4 and 8 wk of treatment. Concanavalin-A responses at 8 wk, but not 4 wk, were suppressed in treated mice. A similar trend was observed for phytohemagglutinin and lipopolysaccharide responses. Evidence was presented that d-limonene had polyclonal activator action. Mice primed with keyhole limpet hemocyanin (KLH) prior to initiation of d-limonene treatment had suppressed primary and secondary anti-KLH responses. Mice treated with d-limonene prior to KLH priming produced significant increased antibody responses. Additional evidence for polyclonal stimulation was obtained by histopathologic examination of secondary lymphoreticular tissue. Significant secondary follicle development and prominent lymphoid nodules and aggregates were found in the pancreas and intestinal mucosa, particularly apparent in mice receiving the highest d-limonene dosage. A subchronic LD50 study was conducted wherein BALB/c mice received 16 daily doses of d-limonene. An LD50 of approximately 0.0850 mg d-limonene/kg (corrected for 82% purity) was determined.     

Stress proteins and the immune response

The heat shock or stress response is one of the most highly conserved adaptive responses in nature. In single cell organisms, the stress response confers tolerance to a variety of stresses including hyperthermia, hyperoxia, hypoxia, and other perturbations, which alter protein synthesis. This tolerance phenomenon is also extremely important in the multicellular organism, resulting in not only thermal tolerance, but also resistance to stresses of the whole organism such as ischemia-reperfusion injury. Moreover, recent data indicates that these stress proteins have the ability to modulate the cellular immune response. Although the terms heat shock proteins (HSPs) and stress proteins are often used interchangeably, the term stress proteins includes the HSPs, the glucose-regulated proteins (GRPs) and ubiquitin. The stress proteins may be grouped by molecular weight ranging from the large 110 kDa HSP110 to ubiquitin at 8 kDa. These proteins serve as cellular chaperones, participating in protein synthesis and transport through the various cellular compartments. Because these proteins have unique cellular localizations, the chaperone function of the stress proteins often involves a transfer of peptides between stress proteins as the peptide is moved between cellular compartments. For example, HSP70 is a cytosolic and nuclear chaperone, which is critical for the transfer of cellular peptides in the mitochondrion through a hand-off that involves mitochondrial HSP60 at the inner mitochondrial membrane. Similarly, cytosolic proteins are transferred from HSP70 to gp96 as they move into the endoplasmic reticulum. The central role of the stress proteins in the transfer of peptides through the cell may be responsible for the recently recognized importance of the stress proteins in the modulation of the immune system [Feder, M.E., Hofmann, G.E., 1999. Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243-282.]. This importance in immune regulation is best addressed using Matzinger's model of the immune response - The Danger Theory of Immunity [Matzinger, P., Fuchs, E.J., 1996. Beyond self and non-self: immunity is a conversation, not a war. J. NIH Res. 8, 35-39.]. Matzinger suggests that an immune system model based on the differentiation between "self and non-self" does not easily account for the changes that occur in the organism with growth and development. Why, for example does an organism not self-destruct when the immune system encounters the myriad of new peptides generated at puberty? Instead, she proposes a model of immune function based on the ability to detect and address dangers. This model states that the basic function of all cells of the organism is appropriately timed death "from natural causes". This type of cell death, or apoptosis, generates no stress signals. If, on the other hand, a cell is "murdered" by an infectious agent or dies an untimely death due to necrosis or ischemia, the cell undergoes a stress response with the liberation of stress protein-peptide complexes into the extracellular environment upon cell lysis. Not only do they serve as a "danger signal" to alert the immune system to the death of a cell under stress, but their role as protein carriers allows the immune effector cells to survey the peptides released by this stressed cell and to activate against new or unrecognized peptides carried by the stress protein. Matzinger bases the Danger Theory of Immunity on three "Laws of Lymphotics". These laws state that: (1) resting T lymphocytes require both antigen stimulation by an antigen-presenting cell (APC) and co-stimulation with a danger signal to become activated; (2) the co-stimulatory signal must be received through the APC; and (3) T cells receiving only antigen stimulation without the co-stimulatory signal undergo apoptosis. The Danger Theory gives a simple model for both tolerance and activation. (ABSTRACT TRUNCATED)     

Regulating the immune response to tumours

Naturally occurring regulatory T cells (Tregs) have been shown to suppress immune responses to self-antigens, thereby limiting autoimmunity. In the case of tumours, where immune responses to self-antigens are beneficial and lead to elimination of the tumour, such suppressive activity is actually detrimental to the host. Manipulation of Tregs holds great promise for the immunotherapy of cancer. Several studies performed using rodent models and indicate that Tregs cells inhibit effective anti-tumour immune responses and that their removal promotes tumour rejection. The increasing number of studies of Tregs in patients with cancer also point to a role for these cells in promoting disease progression. This review summarises the findings of these studies and addresses the advantages and potential pitfalls of manipulating Treg activity for the treatment of cancer.     

Particularities of the immune response in neurocysticercosis

Unique physiological and immunological features of the brain, as previously presented, explain the limitation of local inflammatory reactions and the existence of intrathecal specific IgG production. In addition, some parasitic factors of recent knowledge are induced during neurocysticercosis, which could be involved in vivo in a modulation of the immune response by larval products (a soluble RNA-peptide, some metacestode surface sphingoglycolipids). These recent findings lead us to make a critical review of the antigenic profiles obtained by enzyme-linked immunoelectrotransfer blot (EITB) on samples collected from patients suffering from simple or multiple neurocysticercosis.     

Modulation of innate immune responses in the treatment of sepsis and pneumonia

In the last decades several preclinical models for sepsis have been used to study the pathophysiologic processes during sepsis. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in septic patients were disappointing. It should be realized that most of the preclinical models for sepsis lack a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis with a more natural route of infection, such as pneumonia, and when using models for sepsis lacking an infectious focus. In this review we will compare models for sepsis and models for pneumonia. We advise to use a combination of models, including models for sepsis and models for localized infections, to test new immunomodulating strategies before starting any clinical trial evaluating a new immunomodulating therapy.     

Eugenol modulation of the immune response in mice

The effect of eugenol on selected parameters of the immune response of C57BL/6 mice was studied. In a dose-response study, eugenol at high doses completely inhibited the plaque-forming cell responses of splenocytes to the T-dependent antigen (sheep erythrocytes) both in vitro and in vivo. In vitro, at concentrations higher than 1.0 mM, eugenol was found to be cytotoxic. In vivo, however, at very low doses there appeared to be a suppression of the plaque-forming cell response to sheep erythrocytes, reaching maximal suppression at 0.1 mumol eugenol/kg mouse body weight. This was followed by enhancement of the response, peaking at 0.25 mumol eugenol/kg mouse body weight. These changes correlated fairly well with body weight changes. Thymic weights appeared to remain unchanged for all doses except the 1.0 mumol eugenol/kg body weight, which was significantly (p less than 0.05) higher than the rest of the groups. Natural killer activity at all effector:target ratios (100:1, 50:1, 25:1) was significantly (p less than 0.05) enhanced at both 0.25 and 2.5 mumol eugenol/kg body weight. Overall, eugenol seems to have dose-dependent suppressive and enhancing effects on the immune response. These effects represent an atypical multiphasic response in which an inversed dose-response relationship is observed.     

褪黑素对光暗周期频繁颠错小鼠免疫功能的调节作用

目的研究光暗周期颠倒 (light darkshifting,LDS)对小鼠免疫功能的影响 ,以及褪黑素 (mela tonin,MT)对LDS小鼠的免疫调节作用。方法在建立LDS的动物模型上测定抗体形成细胞(PFC)溶血实验 ,血清溶血素水平 ,迟发超敏反应 ,白细胞数及淋巴细胞百分率及碳粒廓清指数。结果LDS使抗体形成细胞的溶血能力升高 ,血清溶血素水平上调 ,迟发免疫功能亢进 ,白细胞数和淋巴细胞百分率下降 ;MT使LDS小鼠降低的白细胞数及淋巴细胞百分率明显升高 ,下调血清溶血素及PFC水平、迟发超敏反应 ,使之趋于正常 ,对LDS小鼠碳粒廓清能力无显著性影响。结论MT使LDS所致免疫功能异常调节到正常水平。     

Modulation of immune response in mice immunised with an inactivated Salmonella vaccine and gavaged with Andrographis paniculata extract or andrographolide

Gavage of mice, immunised with an inactivated S. typhimurium vaccine, with Andrographis paniculata extract [APE] or andrographolide [AND] resulted in an enhancement of Salmonella-specific antibody response and induction of cell-mediated response against salmonellosis. Mice were vaccinated with either one or two doses of killed S. typhimurium vaccine and fed two different quantities of APE or AND, for 14 days in mice immunised with one dose of the vaccine, and for 28 days in mice immunised with two doses of vaccine, respectively. Both APE and AND were found to enhance IgG antibody levels against S. typhimurium, the enhancement being statistically significant in mice receiving two doses of the vaccine. Splenocyte cultures, prepared from mice immunised with the killed Salmonella vaccine and treated with APE or AND, showed a remarkable increase in the production IFN-gamma following stimulation with the bacterial lysate, indicating an induction of Salmonella-specific cell-mediated response/immune response.     

Cimetidine as modulator of the cell-mediated immune response in vivo using the tuberculin skin test as parameter.

The in vivo pharmacological effects of cimetidine on delayed hypersensitivity reactions in healthy volunteers were studied using the tuberculin skin test as parameter. Cimetidine clearly enhanced this reaction when it was administered well before antigenic stimulation.