Modulation of the immune response by gangliosides. Inhibition of adherent monocyte accessory function in vitro

Gangliosides are potent inhibitors of lymphoproliferative responses. Selectively greater inhibitory effects of gangliosides on antigen-induced (vs. mitogen-induced) proliferation have been documented; e.g., 50 nmol of highly purified bovine brain gangliosides (BBG)/ml caused greater than or equal to 87% inhibition of proliferative responses of human peripheral blood mononuclear cells (PBMC) to three soluble specific antigens (Candida, streptokinase-streptodornase, and tetanus toxoid) vs. less than or equal to 37% inhibition of responses to three nonspecific mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen). The possibility that BBG interfere with adherent monocyte accessory function, upon which responses to soluble specific antigens are strictly dependent, was therefore considered. PBMC were separated into the adherent and nonadherent subpopulations, exposed to BBG, recombined, and their proliferative responses were measured. Unseparated PBMC preincubated for 48-72 h with 100 nmol BBG/ml and then washed to remove unbound BBG exhibited 73-76% inhibition of subsequent antigen-induced lymphoproliferation. Separate pretreatment of both adherent and nonadherent cell subpopulations in BBG under the same conditions resulted in similar (72-82%) inhibition, which was reproduced by preincubation of only the adherent cells in BBG. Preincubation of only the nonadherent cells in BBG was not inhibitory. Inhibition (a) was independent of whether gangliosides were added in solution or incorporated into liposomes, (b) was abrogated by adding untreated monocytes to cultures containing adherent cells that were preexposed to BBG (excluding the possibility that BBG was inducing suppression mediated by adherent cells), and (c) was reversible by further incubation of BBG-pretreated adherent cells in control medium. Together, these results delineate a mechanism by which gangliosides modulate lymphoproliferative responses--direct, noncytotoxic, and ultimately reversible inhibition of the accessory function of adherent monocytes.     

Modulation of L-selectin ligand expression during an immune response accompanying tumorigenesis in transgenic mice.

Immune surveillance depends on lymphocyte access to tissue. Lymphocytes emigrate from blood when adhesion receptors such as L-selectin and the alpha 4 beta 7 integrin on these cells bind to ligands expressed on venular endothelium. Among transgenic mouse lines expressing an oncoprotein (Tag) in islet beta cells, some recognize Tag as nonself. In these mice, Tag expression elicits both beta cell hyperplasia with subsequent progression to tumors and lymphocytic infiltration. Endothelial ligands for L-selectin and alpha 4 beta 7 were upregulated in infiltrated islets in these transgenic mice. These ligands were not expressed in tumors, which were devoid of lymphocytic infiltration. In contrast, the adhesion molecules PECAM-1, ICAM-1, and VCAM-1 were expressed on endothelium in both noninfiltrated tumors and infiltrated islets. Thus, upregulation of expression of endothelial ligands for L-selectin and alpha 4 beta 7 may contribute to autoimmune infiltration. Repression of expression of these same ligands may be involved in the failure of tumor immunity.     

Modulation of the cellular immune response after oral or subcutaneous immunization with microparticles containing Brucella ovis antigens.

An antigenic extract (HS) from Brucella ovis was encapsulated in either poly-epsilon-caprolactone (PEC) or poly-lactic-co-glycolic acid 75:25 (PLGA) microparticles containing beta-cyclodextrin and Pluronic F-68 as stabilising agents. The resulting microparticles displayed sub-5 microm sizes. Antigen loading was 5.2 and 3.8 microg/mg for HS-PEC and HS-PLGA microparticles, respectively. Specific HS cytokine profiles were determined after subcutaneous and oral immunisation of BALB/c mice. Gut distribution studies of the formulations after oral administration showed that HS-PEC microparticles interacted more strongly with mucosa and Peyer's patches than HS-PLGA. Accordingly, oral immunisation with HS-PLGA induced a negligible immune response, whereas HS-PEC elicited a Th1 response although of low intensity. Subcutaneous immunisation with HS-PEC induced high IFN-gamma and IL-2 release; in contrast, HS-PLGA particles induced a Th2 profile characterized by significant levels of IL-4. Splenic cells from free-HS immunised mice released IFN-gamma and IL-2 but not IL-4. A less intense Th1 pattern was also found from HS stimulated nai;ve splenic cells. These results suggest that the HS itself possesses Th1 immunopotentiating properties, required to control brucellosis, that can be specifically increased by encapsulation in PEC microparticles. In contrast, PLGA microparticles modulate the response toward a Th2 pathway.     

Regulation of immune response by cytokine network]

Cytokines are a highly diverse group of intracellular messages. Many cDNAs that encode the cytokines have been cloned in 1980's and the structure of the molecules have been determined. The main function of the cytokines is to amplify the immune and inflammatory responses, keeping them under control at the same time. They orchestrate the response and maintain a proper balance among the various cell types. In this chapter, we summarized the immunoregulation by cytokine network, focussing on the control of antibody production and immunoglobulin class switch by various cytokines produced by helper T cell subsets.     

Suppression of the immune response by alpha-fetoprotein on the primary and secondary antibody response.

Mouse amniotic fluid was shown to contain a noncytotoxic inhibitor of primary gammaM and secondary gammaM, gammaG subclass splenic plaque forming cells in vitro to SRBC. The suppressive effect was not abolished by exhaustive dialysis or by absorption of mouse amniotic fluid (MAF) with SRBC. Polyacrylamide gel analysis showed that dialyzed MAF was composed of three major protein components, transferrin, albumin, and alpha-fetoprotein (AFP). The selective removal of each of these patients from MAF by affinity chromatography suggested that AFP was the immunosuppressive substance in MAF. This conclusion was verified by the demonstration that pure AFP suppressed in vitro antibody synthesis in microgram quantities whereas equivalent amounts of normal mouse serum, transferrin, or albumin did not. Dose-response studies showed that the effect of AFP in the isolated form was equivalent to the suppressive effect of comparable amounts of AFP in MAF. gammaA and gammaG plaque-forming cell (PFC) responses were suppressed by a significantly lower concentration of AFP than was the gammaM PFC response. The degree of suppression watration of AFP than was the gammaM PFC response. The degree of suppression was dependent on the time at which AFP was added to the cultures; MAF added to antigen-stimulated cultures up to 24 h after initiation of cultures was immunosuppressive whereas similar additions of MAF at 48 h after initiation or later did not suppress. The duration of exposure of spleen cells to MAF in cultures without antigen necessary to achieve suppression of a subsequent primary immune response was determine-d to be approximately 8 h. The results suggest that AFP may have an immunoregulatry function. This has potentially important implications in the maternal-fetal relationship, the immune capabilities of the fetus and newborn, and in certain malignant and nonmalignant diseases in which AFP is elevated.     

化疗对机体免疫细胞的调节

肿瘤的发生、发展及转移与机体的免疫细胞的功能密切相关,到目前为止,肿瘤的治疗方法仍然以化疗为主,以往的研究一直认为化疗在杀伤肿瘤细胞的同时,抑制了机体的免疫系统,近期一系列研究证明化疗药物通过降低Treg细胞的数量,诱导树突状细胞(DC)成熟等增强机体免疫细胞功能的途径而提高机体抗肿瘤的作用,根据化疗后免疫细胞功能的变化,优化化疗联合免疫治疗方案,这为化疗联合免疫治疗带来了新的突破点,本文综述常见化疗药物对机体免疫细胞功能的影响。     

Bacampicillin and the immune response

To evaluate the possible influence of a bacampicillin on the immune response, 16 subjects, out of a group of 60 patients with bacterial respiratory tract infections, had various tests of immune function determined, before and after treatment. The peripheral mononuclear blastogenic index (ratio between PHA-induced and spontaneous proliferation), PHA-induced interferon-gamma production, percentages of T and B lymphocytes, serum immunoglobulins (IgG, IgM, IgA) levels, failed to show any significative differences before and after the treatment with bacampicillin. The PHA-induced interleukin-2 production increased after treatment but just failed to reach statistical significance (0.1 less than P less than 0.05; t = 1.9). The clinical condition of 56 of the sixty (93.3%) treated patients improved and neither side-effects nor alterations of liver or kidney function were observed. This study has shown no inhibitory effect of bacampicillin on the immune response while confirming its clinical efficacy.     

Cellular immune response profile in patients with American tegumentary leishmaniasis prior and post chemotherapy treatment

In this study, we have the objective of evaluating the lymphoproliferative response and determining interferon (IFN)‐γ and interleukin (IL)‐10 cytokine production in the peripheral blood mononuclear cells (PBMC) of patients with American tegumentary leishmaniasis prior and post 12 months of chemotherapy treatment with meglumine antimoniate compared with the PBMC of noninfected donors. Lymphoproliferation, such as cytokine production, was evaluated through in vitro stimulus with the soluble antigenic fraction from Leishmania (Viannia) braziliensis promastigotes (1.25 µg/ml) and Concanavalin A (2.5 µg/ml). Patients showed a significant lymphoproliferative response prior and post treatment compared with the control group. Similar result, prior to chemotherapy treatment, was observed in IFN‐γ and IL‐10 production when patients were compared with the control group. After chemotherapy treatment, PBMC lymphoproliferative response of the patients revealed an increase, whereas patients have shown a decrease in IFN‐γ levels and an increase in IL‐10, although without statistical difference. These results may indicate that the patients produced a specific cellular response to the soluble antigenic fraction suggesting that besides Th1 and Th2 dichotomy, immunological regulation mechanisms with the participation of memory T cells and regulatory T cells could be present in the clinical evolution of these patients. This understanding will allow the study and identification of new L. (V.) braziliensis molecules potentially candidates to vaccines. J. Clin. Lab. Anal. 23:63–69, 2009. © 2009 Wiley‐Liss, Inc.     

Modulation of T-cell-mediated regulation of antibody production by interaction with specific immune complexes

The importance of the phlogogenic effects of immune complexes in disease pathogenesis has been emphasized, but they also have a role in immunoregulation. We examined the effects of DNA: anti-DNA immune complexes, formed at different antigen:antibody ratios, on the ability of T cells to modulate DNA antibody production in vitro. We found that antigen-excess complexes promote IgM anti-DNA synthesis, whereas antibody-excess complexes favor a switch to IgG anti-DNA production. We suggest that interaction of T cells with immune complexes is an important feedback mechanism in control of the immune response.     

Modulation of the primary and the secondary antibody response by tobacco smoke condensates.

Cigarette smoke condensate administered to C57BL/6 mice led to a decrease in the primary antibody response to OVA (hen egg albumin) antigen. Selenium (Se)-supplementation allowed to relieve significantly this inhibition. Moreover, even being not supplemented with Se, a preparation was found devoid of inhibitory effects. Furthermore, the presence of Se-supplemented tobacco smoke condensate at the time of antigen priming, contributed to an enhanced secondary antibody response.     

Modification of immune response in mice by ciprofloxacin.

Some studies have suggested that the addition of ciprofloxacin to in vitro cultures of mitogen-stimulated lymphocytes exerts inhibitory effects on cell cycle progression and immunoglobulin (Ig) secretion. We tested the effects of this drug on some immunity parameters in BALB/c mice. Mice treated intraperitoneally with ciprofloxacin (10 mg/kg of body weight per day) for 3 consecutive days and immunized with sheep erythrocytes 24 h after the last injection showed significant suppression of hemolytic IgG-forming cells, whereas the response of IgM-forming cells remained unchanged. When treatment lasted 7 days the response of antibody-forming cells was not modified. When the 3-day treatment was started at 24 h after immunization with sheep erythrocytes, the response of IgM-forming cells was increased, whereas the response of IgG-forming cells was suppressed. Delayed-type hypersensitivity to sheep erythrocytes was significantly suppressed in animals that received the 3-day treatment with ciprofloxacin and were immunized subcutaneously 24 h after the last injection. In vitro proliferation of lymphocytes from ciprofloxacin-treated mice in response to either lipopolysaccharide or concanavalin A was also suppressed. Leukopenia and an increase in the level of granulocyte-macrophage colony-forming cells in bone marrow were also observed in ciprofloxacin-treated mice. These results, together with those from other reports, suggest that modification of the biological responses by ciprofloxacin is a complex phenomenon that may be influenced by several factors.     

Functional reprogramming of the primary immune response by T cell receptor antagonism

The T cell receptor must translate modest, quantitative differences in ligand binding kinetics into the qualitatively distinct signals used to determine cell fate. Here, we use mice that express an endogenous T cell receptor (TCR) antagonist and an adoptive transfer system to examine the influence of TCR signal quality on the development of effector function. We show that activation of antigen-specific T cells in the presence of an antagonist results in a functional reprogramming of the primary immune response, marked by altered T cell homing, a failure to develop effector function, and ultimately clonal elimination by apoptosis. Importantly, antagonism does not block cell division, implying that the signals promoting clonal expansion and effector differentiation are distinct.     

A calculated response: control of inflammation by the innate immune system

Inflammation is a rapid yet coordinated response that can lead to the destruction of microbes and host tissue. Triggers capable of inducing an inflammatory response include tissue damage and infection by pathogenic and nonpathogenic microbes. Each of these triggers represents a qualitatively distinct stress to the host immune system, yet our understanding of whether they are interpreted as such remains poor. Accumulating evidence suggests that recognition of these distinct stimuli converges on many of the same receptors of the innate immune system. Here I provide an overview of these innate receptors and suggest that the innate immune system can interpret the context of an inflammatory trigger and direct inflammation accordingly.     

Stimulation of the immune response by dimethylglycine, a nontoxic metabolite.

The immunomodulating capacities of dimethylglycine (DMG) were examined in a rabbit model. Female New Zealand white rabbits were immunized on day 0 and were given booster inoculations on day 9 with either killed influenza virus or Salmonella typhi vaccine. Experimental animals were force fed 20 mg/kg body weight of DMG daily beginning 14 days prior to the first inoculation and continuing throughout the experiment. Control animals were force fed daily only distilled water. Blood was obtained on day 0, day 9, and day 30. Hemagglutination inhibition assays showed a more than fourfold increase in mean antibody titer to influenza antigen in the DMG-treated animals (p = 0.0006) after the first inoculation, and a fourfold increase in mean titer after the booster inoculation (p = 0.1000). A standard agglutination test for Salmonella typhi O (somatic) and H (flagella) antigens was performed on all sera from animals receiving the typhoid vaccine. Mean antibody titers to the O antigen were significantly higher (more than threefold) after the first inoculation (p = 0.0302) and more than fivefold higher after the booster inoculation (p = 0.0047) in DMG-treated animals. Mean antibody titers to the H antigen were also higher in DMG-treated animals compared with controls after both the first and second inoculation. Lymphocyte transformation assays on cells taken from DMG-treated animals immunized with the influenza vaccine showed a tenfold increase in mean proliferative response (p = 0.0024). Lymphocytes from DMG-treated animals immunized with the typhoid vaccine showed a fourfold increase (mean values) in thymidine uptake (p = 0.0180). No toxicity or adverse effects were observed at any time during the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)