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PubMedDate not supplied

T1/ST2--an IL-1 receptor-like modulator of immune responses.

Th2-associated factors such as IL-4 are involved in both the development of Th2 responses (via modulating Th2 cell differentiation) and in the effector phase of Th2 responses (via modulating macrophage activation). The IL-1 receptor-like protein ST2 (T1, Fit-1, or DER4) is expressed as a membrane-bound (ST2L) or secreted form (sST2), and has been clearly implicated as a regulator of both the development and effector phases of Th2-type responses. Here we analyze the mechanisms and therapeutic implications of the unique ability of ST2 to promote development and function of type 2 helper T cells through a positive feedback loop, as well as to act as a negative feedback modulator of macrophage pro-inflammatory function.

Animals↗

PubMed2005

Multi-organ transplantation: is there a protective effect against acute and chronic rejection?

BACKGROUND: Heart-lung transplantation (Tx) is known to offer a protective effect against acute cardiac rejection. This study was undertaken to evaluate acute and chronic heart and/or lung rejection in the setting of multiple-transplanted organs from the same donor compared with single-organ transplantation. METHODS: Acute (treated rejection episodes of heart or lungs) and chronic (allograft vasculopathy in hearts and bronchiolitis obliterans syndrome [BOS] in lungs) rejection events were analyzed in 348 heart transplant (H) recipients, 24 heart-lung (HL) recipients, 82 double-lung (L) recipients and 8 heart-kidney (HK) recipients >18 years of age, who were transplanted between 1990 and 2002. RESULTS: Survival at 3 years differed among groups as follows: HK, 100%; H, 82%; HL, 74%; and L, 70%. The probability of acute rejection within the first 3 months was higher in H recipients than in HL (81% vs 22%; p < 0.0001) or HK (81% vs 12%; p = 0.00009) recipients. Acute cardiac rejection occurred more frequently during the first 2 years in isolated H recipients compared with HL (2.8 vs 0.27 episodes; p < 0.0001) and HK (2.8 vs 0.54; p < 0.001) recipients. Acute lung rejection occurred more frequently in the first 2 years in L than HL (2.4 vs 1.0 episodes; p = 0.02) recipients. Chronic cardiac rejection (allograft vasculopathy) was more likely within 3 years after H compared with HL (32% vs 16%; p = 0.04) or HK (32% vs 0%; p = 0.14). The onset of chronic lung rejection (BOS) within 3 years was similar in HL and L recipients (39% vs 40%; p = 0.9). CONCLUSIONS: Recipients of multiple organs from a single donor undergo less acute rejection of the heart or lungs compared with isolated heart or lung transplant recipients. Cardiac allograft vasculopathy is decreased significantly when cardiac transplantation is combined with a lung allograft. A lower incidence of cardiac allograft vasculopathy is observed when cardiac transplantation is combined with a renal allograft, and may prove statistically significant when more cases have been accumulated. These phenomena may result from immune modulation of the recipient by simultaneous transplant of disparate tissues or introduction of immune-modulating hematopoietic elements.

Acute Disease↗

PubMed1996

The role of calcium-channel antagonists in solid organ transplantation.

Calcium-channel antagonists play a role not only in the management of cardiovascular disease, but they may also play a role in solid organ transplantation. Part of the success of solid organ transplantation over the last several years has been the development of potent immunosuppressive agents such as cyclosporine A and tacrolimus. The calcium-channel antagonists have been shown to decrease cyclosporine A-induced nephrotoxicity by blocking the vasoconstrictive effects of endothelin and thromboxane A2 on the afferent arteriole induced by this agent. The role of calcium antagonists in avoiding tacrolimus-induced nephrotoxicity has not been studied to date. Calcium antagonists have been shown to have an immune-modulating effect as well, via inhibition of calcium-mediated lymphocyte proliferation. This immune-modulating effect has resulted in a decreased incidence of acute rejection in those patients receiving concomitant cyclosporine and calcium antagonists. A third role for calcium antagonists in organ transplantation has been as an additive to organ preservation solutions to avoid calcium-mediated ischemic damage. Despite several successful investigations demonstrating a role for calcium antagonists in solid organ transplantation, widespread acceptance of such a role awaits larger randomized clinical trials.

Animals↗

PubMed2002

Immune response modulation by recombinant peptides expressed in virus-like particles.

Aspergillus fumigatus, a ubiquitous fungus, is implicated in the pathogenesis of a number of clinically different allergic diseases in man, including allergic bronchopulmonary aspergillosis. Peptide-based immunotherapy may offer an alternative treatment strategy for the management of allergic disease. The objective of this study was to alter the allergen-specific immune response using dominant T cell epitopes of a major A. fumigatus allergen, Asp f2, expressed in yeast as virus-like particles (VLP). The T cell epitopes of Asp f2, recognized in mice with an H-2d background, were determined by producing T-cell hybridomas. Two dominant T cell epitopes, aa60--71 and aa235--249, were identified and expressed in a yeast VLP system. To induce tolerance VLP-peptides were injected subcutaneously into mice previously immunized with recombinant Asp f2. The T cell immune response was abrogated totally in 3 weeks following a single injection of VLP but was restored 2 months later following intranasal antigen exposure. T-cell depletion resulted in the reduction of 20-30% of all antigen-specific immunoglobulin classes. Thus, recombinant peptides expressed in the VLP system can be used successfully in the modulation of Asp f2-induced immune response in mice, although a single administration is not sufficient to maintain a state of tolerance for a long period of time.

Allergens↗

PubMed2005

Inulin, oligofructose and immunomodulation.

Diet is known to modulate immune functions in multiple ways and to affect host resistance to infections. Besides the essential nutrients, non-essential food constituents such as non-digestible carbohydrates may also have an impact on the immune system, especially in the area of the gut-associated lymphoid tissue (GALT). Recent data now provide first evidence that prebiotics such as inulin/oligofructose (IN/OF) modulate functions of the immune system. In animal studies IN/OF primarily activated immune cells in Peyer's patches including IL-10 production and natural killer (NK) cell cytotoxicity. Other immune functions modulated by IN/OF included the concentration of secretory IgA in ileum and caecum, splenic NK cell cytotoxicity as well as splenocyte cytokine production. In different tumour models, a lower incidence of tumours was observed, which in the case of colonic tumours was associated with enhanced NK cell cytotoxicity in the GALT. Few human studies so far have investigated the effects of IN/OF alone or in combination with other dietary supplements on immunocompetence. Supplementation of IN/OF resulted in minor changes of systemic immune functions such as decrease in phagocytic activity. No data are available on the effects of IN/OF on the GALT in man. The mechanisms of the reported effects of IN/OF on the immune system are currently investigated and include: (i) direct effects of lactic acid-producing bacteria or bacterial constituents on immune cells; (ii) the production of SCFA and binding to SCFA receptors on leucocytes. In conclusion, the current data suggest that IN/OF primarily modulate immune parameters in the GALT, but splenocytes are also activated by IN/OF. Human studies are needed to find out whether IN/OF have the potential to modulate systemic immunity in well-nourished individuals and to lower the risk of diseases such as colon cancer.

Animals↗

PubMed2002

Therapeutic prospects for early asthma.

What we know: There is strong evidence that T cells contribute to asthma pathogenesis. Immune-modulating drugs that dampen, turn off or redirect T cells, and adjuvants that trigger T(H)1 immune responses, are potential therapies for preventing asthma. Current T cell immune suppressors are too toxic to use in very young children with asthma. Immune-modulation research is identifying pathways that might lead to preventive therapy for asthma. Inhibitors of T cell cytokines do not reduce asthma in adults. What we need to know: Is immune deviation from a T(H)2-type response towards a T(H)1-type response a sound strategy given that mixed T(H)1/T(H)2 responses are already known to occur in asthma? What, specifically, triggers the development of armed effector lymphocytes that are thought to cause tissue damage in asthma? Are the changes in lung structure that are observed in chronic asthma really dependent on T cell mechanisms? Can abnormal lung structure be improved or normalised? Would any of these strategies be safer and more effective than current therapies?

Animals↗

PubMed1985

Network regulation of the immune response: modulation of suppressor lymphocytes by alternative signals including contrasuppression.

In the preceding paper we demonstrated that comparison of alternative designs for the immune network can be used to examine the functional significance of specified interactions in normal immune responses. In this paper we examine mathematically the functional significance of three interactions affecting the production of suppressor lymphocytes involved in regulation of normal immune responses. The interactions examined in detail are 1) antigenic stimulation of the production of suppressor lymphocytes, 2) idiotypic stimulation of the production of suppressor lymphocytes, and 3) antigenic inhibition of the production of suppressor lymphocytes (i.e., contrasuppression). The results of our analysis suggest that an immune system with only antigenic stimulation of suppressor production is less effective than a system with both antigenic and idiotypic stimulation of suppressor production on the basis of all of the criteria examined in this study. In turn, the latter system is less effective than a system with only idiotypic stimulation of suppressor production. Furthermore, a system with both idiotypic stimulation and antigenic inhibition of suppressor production can be equal or superior to a system with only idiotypic stimulation of suppressor production on the basis of the same criteria. Similar conclusions hold for the comparison of systems in which regulation by the suppressor lymphocytes of interest is exerted upon production of effector molecules rather than upon production of effector lymphocytes, and also for the comparison of systems in which interactions affecting the production of suppressor factors are of interest.

Animals↗

PubMed1996

Modulation of immune responses by bovine beta-casein.

The present reports the influence of bovine beta-casein on in vitro and in vivo immune responses. Bovine beta-casein showed an inhibitory effect on ovine neutrophil chemotaxis but had an enhancing effect on superoxide production by neutrophils. In response to mitogenic stimulation, the proliferative response of both T and B lymphocytes was significantly enhanced by beta-casein. While beta-casein had no significant effects on IFN gamma production by ovine blood lymphocytes, and TNF alpha production and MCH Class II antigen expression by ovine bronchoalveolar macrophages, it enhanced IL-1 beta production by the macrophages, beta-casein also had no influence on bovine NK cell activity against a virally-infected cell line. Interestingly, beta-casein was found to reduce the adjuvant effect of matrix immune stimulating complexes (ISCOM) on anti-ovalbumin antibody response in mice when given intramuscularly. Taken together, the results suggest that bovine beta-casein had selective modulating effects in vitro on both innate and adaptive immune responses in ruminants, whereas systemic administration of beta-casein, that might have a depressive effect on adjuvant activity, requires further study.

Animals↗

PubMed2004

Immunotherapy with agonistic anti-CD137: two sides of a coin.

CD137 (4-1BB), a member of the TNF receptor superfamily, is an inducible T cell costimulatory receptor primarily expressed on activated CD4+ and CD8+ T cells. Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses. Surprisingly, these agonists also showed therapeutic effects in several autoimmune diseases. These findings suggest that in different disease environments, CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes. Therefore, CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders. However, CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically.

Animals↗

PubMed2003

Prospects for vitamin D receptor modulators as candidate drugs for cancer and (auto)immune diseases.

The development of less calcemic vitamin D analogs creates possible therapeutic applications for immune modulation (e.g., autoimmune diseases and graft rejection), inhibition of cell proliferation and induction of cell differentiation (e.g., cancer). Recently more insight was obtained in the mechanism of action of the analogs at the biological and molecular level. Critical remarks are summarized on why the step towards the clinic has not yet been taken and how better selective vitamin D receptor modulators could be designed.

Animals↗

PubMed2004

3D molecular modeling, free radical modulating and immune cells signaling activities of the novel peptidomimetic L-glutamyl-histamine: possible immunostimulating role.

An original representative of the patented by author family of histamine-containing peptidomimetics L-glutamyl-histamine (L-Glu-Hist) was synthesized and characterized as a biologically active compound with a role of cytokine mimic leading to cellular responses of improved specificity. The study assesses the ability of L-Glu-Hist to affect molecular modeling, modulate free radical activity and influence immune cell signaling. The energy-minimized 3D conformations of L-Glu-Hist derived from its chemical structure resulted in stabilization for Fe2+ chelating complexes. L-Glu-Hist accelerated the decrease of ferrous iron in the ferrous sulfate solution in a concentration-dependent mode and showed the ferroxidase-like activity at concentrations less than 3 mM in the phenanthroline assay, whereas in the concentration range 3-20 mM L-Glu-Hist restricted the availability of Fe2+ to phenanthroline due to binding of ferrous ions in chelating complexes. L-Glu-Hist showed stimulatory effect on phosphatidylcholine liposomal peroxidation (LPO) catalyzed by the superoxide anion radical (O2*-)-generating system (Fe2+ + ascorbate) at low (less or about 1 mM) L-Glu-Hist concentrations and both revealed the inhibitory effect on LPO in this system of high (approximately 10 mM) L-Glu-Hist concentration. The stimulation of LPO by L-Glu-Hist was related to the ability of peptidomimetic in small (approximately 0.05 mM) concentrations to release O2*- free radicals as determined by the superoxide dismutase-inhibitable cytochrome c reduction assay. O2*- release by L-Glu-Hist might result from its ferroxidase-like activity, while inhibition of LPO by L-Glu-Hist was caused by its chelating activity to Fe2+ ions, prevention of free radical generation and lipid hydroperoxide-degrading ability of 5-20 mM L-Glu-Hist. L-Glu-Hist released O2*- in concentrations which stimulated [3H]-thymidine incorporation into DNA and proliferation of mouse spleen lymphocytes and mononuclear cells from human blood. L-Glu-Hist modulates the ability of oxygen free radicals to act as signaling agents at low concentrations, influencing gene expression. The structural peptide-like analogues of L-Glu-Hist such as L-Glu-Trp, carcinine (beta-alanylhistamine), but not L-Pro-Glu-Trp were active in stimulating thymidine incorporation and in inducing proliferation of mononuclear cells as compared to mitogen concanavalin A at doses 2.5-25.0 microg/ml. Our data provide evidence that L-Glu-Hist may act as a very fast, specific and sensitive trigger for lymphocyte proliferation and immunoregulation. The cited abilities and further obtained in vivo results make Immudilin ((INCI: glutamylamidoethyl imidazole, aqueous solution), L-Glu-Hist) a useful immunoregulatory agent.

Adjuvants, Immunologic↗

PubMed2004

Humoral immune factors modulated by copper and chitosan in healthy or parasitised carp (Cyprinus carpio L.) by Ptychobothrium sp. (Cestoda).

As an environmental protection point of view, the potential toxicity of chitosan on aquatic animal health, alone or associated with copper must be investigated. Fish possess defence mechanisms to counteract the impact of toxics. The non-cellular and non-specific immune defences (total immunoglobulin, ceruloplasmin, lysozyme and potential killing activity of phagocytic cells) can be modulated by the potential environmental pollutants but also by natural stimulants such as bacteria, viruses or parasites. In this study, we investigate the potential toxicity of copper (0.1 and 0.25 mg/L) or chitosan (75 and 150 mg/L) and the combination copper and chitosan (0.1 and 75 mg/L, respectively) on two groups of carp: healthy or parasitised by Ptychobothrium sp. Fish exposed to water-soluble chitosan for 96 h had significantly high levels of natural antibodies in plasma. Moreover, activities of lysozyme and ceruloplasmin were also increased in plasma after the same treatment. The exposition of fish to copper have shown apparently contradictory effects on the immune parameters measured but, significant increase of this bacteriolytic activity was observed, particularly in head kidney after 4 days of treatment of fish with copper. The two products may induce separately an acute, short and local inflammatory acute phase response by stimulating some components of the innate immune response of healthy fish. The mixture seems to reduce the impact of the each product due to the physical and chemical properties of chitosan to complex with copper. The responses of humoral immune factors of treated carp was modulated by the presence of the parasite, as shown by the high elevation of lysozyme activity observed in parasitised carps after exposition to copper and by increases in natural antibodies levels observed in parasitised carp treated with the copper-chitosan mixture. This could indicate an additive effect on the stress response mediated by parasite. It occurred a greater stress response in the parasitised group than healthy group exposed to the same treatment evoking an additive effect. So, it is important to specify the health status of organisms to understand responses of immunological markers in fish.

Animals↗

PubMed2001

Modulation of immunity against herpes simplex virus infection via mucosal genetic transfer of plasmid DNA encoding chemokines.

In this study, we examined the effects of murine chemokine DNA, as genetic adjuvants given mucosally, on the systemic and distal mucosal immune responses to plasmid DNA encoding gB of herpes simplex virus (HSV) by using the mouse model. The CC chemokines macrophage inflammatory protein 1beta (MIP-1beta) and monocyte chemotactic protein 1 (MCP-1) biased the immunity to the Th2-type pattern as judged by the ratio of immunoglobulin isotypes and interleukin-4 cytokine levels produced by CD4(+) T cells. The CXC chemokine MIP-2 and the CC chemokine MIP-1alpha, however, mounted immune responses of the Th1-type pattern, and such a response rendered recipients more resistant to HSV vaginal infection. In addition, MIP-1alpha appeared to act via the upregulation of antigen-presenting cell (APC) function and the expression of costimulatory molecules (B7-1 and B7-2), whereas MIP-2 enhanced Th1-type CD4(+) T-cell-mediated adaptive immunity by increasing gamma interferon secretion from activated NK cells. Our results emphasize the value of using the mucosal route to administer DNA modulators such as chemokines that function as adjuvants by regulating the activity of innate immunity. Our findings provide new insight into the value of CXC and CC chemokines, which act on different innate cellular components as the linkage signals between innate and adaptive immunity in mucosal DNA vaccination.

Animals↗

PubMed2001

Fc-signalling in the modulation of immune responses by passive antibody.

Passive antibody can both suppress and augment immune responses. Until recently, there was virtual unanimity on the importance of the interaction of the Fc portion of modulating antibody with Fc-receptors (Fc-signalling), especially in experiments involving the suppression by antibody. Experiments reported in the last few years, that do not demonstrate the range of Fc-portion/Fc-receptor influences on the suppression of immune responses by passive antibody, have introduced new uncertainty into this field. The purpose of this paper is to review how the initial controversy on the influence of Fc-signalling in inhibition by passive antibody was resolved. Old and new approaches are suggested that may help in resolving the current uncertainty engendered by recent experimental results that were interpreted to mean that passive suppressive antibody does not utilize the inhibitory FcgammaRIIB receptor. An understanding of the factors that influence negative Fc-signalling is needed in order to optimize clinical therapies whose action depends on the suppressive property of antibody.

Animals↗

PubMedDate not supplied

[Experimental study of the immunomodulator effect of pentoxifylline in bacterial translocation produced by lipid-free parenteral nutrition].

INTRODUCTION: Bacterial translocation (BT) leads to sepsis of intestinal origin and, despite current advances, there is a high level of mortality and morbidity as a result of this. We have attempted to investigate whether such an immunity modulating substance as Pentoxiphylline (PX) might diminish or inhibit BT. We have chosen PX because it has immunity modulation actions and inhibits the synthesis and action of TNF-alpha, which seems to be linked to the progress of these conditions towards multiple organ failures. MATERIAL AND METHOD: An experimental study was performed with 4 groups of 20 Wistar rats subjected to lipid-free parenteral nutrition (PN) over 7 days. Group A: PN; group B: PN + 50 mg/kg of PX; group C: PN + 100 mg/kg; and group D: PN + 134 mg/kg. On day 7, a sterile extraction was effected to remove the mesenteric ganglial chain, liver, blood and intestine, and these samples were processed for the quantitative and qualitative microbiological study, the histological study of the intestinal mucosa and the quantification of TNF-alpha. The data obtained were subsequently analyzed statistically. RESULTS: The quantitative microbiological study revealed that, with statistically significant differences, more colonies grew in the lymphatic ganglion, liver and blood of animals belonging to group A. The germ most frequently identified was E. Coli. In the study of TNF-alpha, the greatest value corresponded to group A, again with statistically significant differences. In the histological study, it was observed that group A showed the greatest atrophy. CONCLUSIONS: Our experimental model is valid as a model of BT, in group A, without PX, a total of 16 BT occurred while in the groups with PX the number of BT fell, as did the serum figures for TNF-alpha.

Adjuvants, Immunologic↗

PubMed1995

Modulation of immune function and cytokine production by various levels of vitamin E supplementation during murine AIDS.

Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine AIDS which is functionally similar to human AIDS. Dietary supplementation, with a 15-, 150- and 450-fold increase of vitamin E in a liquid diet, significantly restored levels of interleukin-2 (IL) and interferon-gamma produced by splenocytes, which were suppressed by retrovirus infection. Retrovirus infection elevated levels of IL-6 and IL-10 produced by splenocytes, which were significantly normalized by all levels of vitamin E supplementation, respectively. Increased levels of IL-6 and tumor necrosis factor-alpha, produced by splenocytes during progression to murine AIDS, were also significantly normalized by all levels of vitamin E supplementation. Vitamin E supplementation restored retrovirus-suppressed splenocyte proliferation and natural killer cell cytotoxicity. Vitamin E supplementation also alleviated the AIDS symptoms: splenomegaly and hypergammaglobulinemia. These data indicate that dietary vitamin E supplementation at extremely high levels was not immunotoxic, and can modulate cytokine release and normalize immune dysfunctions during progression to murine AIDS. It should favorably affect host resistance and thereby retard the development of AIDS.

Animals↗

PubMedDate not supplied

Acetone in drinking water does not modulate humoral immunity in mice as measured by the antibody, plaque-forming cell assay.

It has been reported that the repeated topical, nonoccluded application of acetone may modulate antibody production in mice, thus producing humoral immunosuppression. However, the evaporative loss expected following nonoccluded dermal application of acetone makes the systemic effect seem unlikely. This study was designed to investigate the immunotoxicity potential of acetone in mice following a more direct systemic route of dosing via drinking water for 28 days. CD-1 male mice consumed average daily acetone doses of 121, 621 or 1144 mg/kg/day. The antibody, plaque-forming cell (AFC) assay was performed to measure the T cell-dependent, anti-sheep red blood cell immunoglobulin M (IgM) response, and hematology and thymus weights were evaluated to provide additional insight into the potential effects to the immune system. Body weights, white blood cell (WBC), numbers, red blood cell (RBC) counts, and hemoglobin and hematocrit levels showed no treatment-related effects at any dose of acetone. Eosinophil percentages were variable but also showed no dose-related trends. Spleen and thymus weights were not statistically different from controls and there were no effects on spleen cellularity or AFC response as a result of acetone administration. The AFC responses ranged from 1088 to 1401 AFCs/10(6) splenocytes and were not statistically different from controls (1277 AFCs/10(6) cells). Mice treated with cyclophosphamide (20 mg/kg) on days 25 to 28 demonstrated a 94% reduction in AFC/10(6) cells. Thus, the direct systemic administration of acetone did not produce evidence for immunotoxicity in CD-1 mice and the no observed adverse effect level (NOAEL) in this study was determined to be 1144 mg/kg/day.

Acetone↗

PubMedDate not supplied

[Modulation of immune system cells by lactobacilli].

The influence of lactobacilli on the proliferative potential of immune system cells after the intragastral administration of viable microbial cells and their native filtrates to mice CBA is evaluated. The data have been obtained on the modulating influence of lactobacilli on the formation of T- and B-cell immune response--their role in maintaining homeostatsis and specific features of cell mediated immune reactions after the intragastral administration of virulent Shigella dysenteriae for modeling experimental infection in CBA mice. The mechanisms of the immunomodulating action of lactobacilli on local and systemic reactions of the host as well as realization of the protective properties of lactobacilli against the causative agents of acute enteric infections are discussed.

Animals↗