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Genetic correlation between melanization and antibacterial immune responses in a natural population of the malaria vector Anopheles gambiae.

The immune system of invertebrates can mount different responses, including melanotic encapsulation and several antibacterial defense mechanisms. Variation of the efficacies of these responses is generally considered to be a product of the evolutionary pressure on each response due to infection by parasites. However, potential interactions and trade-offs among the different responses of the immune system could constrain the evolutionary potential of each response. In a natural population of the mosquito Anopheles gambiae, we measured the genetic association between the melanization response and an antibacterial response in two environmental qualities (well-fed and undernourished larvae). In both environments the two immune responses were positively genetically correlated: in full-sib families that were most likely to melanize a bead, injected bacteria were most likely to be cleared. Thus, our data do not support the idea of a trade-off among different outcomes of the invertebrate immune system, but rather that some families are overall immunologically superior to others.

Analysis of Variance↗

Prechallenge high neutralizing antibodies and long-lasting immune reactivity to gp41 correlate with protection of rhesus monkeys against productive simian immunodeficiency virus infection or disease development.

To investigate the protective efficacy of various gp130 vaccine preparations, rhesus monkeys were immunized with gp130 oligomers (O-gp130) or two different gp130-monomer preparations (M1-gp130; M2-gp130) and challenged with 50 MID50 of simian immunodeficiency virus (SIV)mac32H. Following challenge the control animals and all animals of the M1- and M2-gp130 group and 1 animal of the O-gp130 group were productively infected, whereas 3 animals of the O-gp130 group resisted the productive virus replication. The protection was correlated with high neutralizing antibodies and a long-lasting immune response to the transmembrane protein gp41. Whereas none of the O-gp130 animals had developed disease symptoms, 3 M1-gp130 animals, 1 M2-gp130 animal, and 2 control animals died as a result of AIDS within 18 months after challenge. Therefore, immunization with virion-derived gp130 oligomers of SIVmac32H can confer protection against the productive infection with SIVmac32H and suppress the development of the AIDS-like disease.

Animals↗

Personality, endocrine and immune changes after eight months in healthy individuals under normal daily stress.

The impact of stress and its neuroendocrine correlates on immune function are well established and individual variations could be attributed to modulation by personality characteristics. To assess the influence of everyday life stress and personality on neuroendocrine and immune function, we administered, to 18 healthy adults, the Minnesota Multiphasic Personality Inventory (MMPI) to assess their personality, the State-Trait Anxiety Inventory to measure anxiety, the Reaction Scheme Test to assess their coping reaction style, the Life Events Survey to assess the impact of stressful life events, and the Subjective Stress Questionnaire to assess perceived stress. The endocrine evaluation comprised prolactin, cortisol, and growth hormone plasma levels, while the immunological evaluation assessed T4, T8, and T11 lymphocyte percentages, as well as natural killer cell count and activity. All evaluations were made at baseline and after 8 months. We found a reduction of the T11 lymphocyte percentage to be accompanied by a reduction in the scores of the MMPI scale of Subtle Defensiveness and by an increase in the scores of the Social Introversion Scale. A positive correlation was found between prolactin and T4 lymphocyte percentage. These preliminary data show that some personality and endocrine measures correlate with immune function.

Adult↗

Tumor necrosis factor alpha (TNF-alpha) production in mice immunized with Escherichia coli: correlation with mortality after lethal challenge and production of a native inhibitor of TNF-alpha activity.

The kinetics of tumor necrosis factor alpha (TNF-alpha) production, the correlation between cytokine levels and mortality rates after lethal challenge, and the production of a native inhibitor of TNF-alpha activity was investigated in mice immunized with formalin-killed Escherichia coli. Groups of mice were injected for 8 weeks with either untreated bacteria or bacteria treated with 0.5 MIC of aztreonam and subsequently challenged with 100 50% lethal doses of viable E. coli. Mice receiving saline only (controls) died within 24 h. The mortality of mice immunized with aztreonam-treated E. coli was significantly lower than that of mice immunized with untreated E. coli. There were no measurable levels of TNF-alpha in sera obtained from control mice during the entire period of immunization. TNF-alpha levels ranging from 90 to 306 U/ml were measured 90 min after each vaccination in sera obtained from mice immunized with untreated E. coli. Sera from mice immunized with antibiotic-treated E. coli showed lower TNF-alpha levels, ranging from 40 to 128 U/ml. TNF-alpha levels measured 90 min after lethal challenge correlated with the mortality rate observed in each group (r = 0.95). The cytotoxic activity of recombinant murine TNF-alpha was inhibited by the sera from immunized mice but not by the sera from controls. The inhibition was drastically reduced by preincubation of the sera with staphylococcal protein A. In immunoblot experiments, class G immunoglobulins reacting with recombinant murine TNF-alpha were observed in the sera of immunized mice. These data confirm the correlation existing between TNF-alpha levels and mortality and suggest that native inhibitors may play a role in the regulation of the biological function of the cytokine.

Animals↗

Immunization with native surface protein NcSRS2 induces a Th2 immune response and reduces congenital Neospora caninum transmission in mice.

NcSRS2, a tachyzoite surface protein of Neospora caninum, is an immunodominant protein with respect to induction of antibody production and has a role in attachment and invasion of host cells. Native NcSRS2 was isolated from whole tachyzoite lysate antigen by affinity chromatography using NcSRS2 specific monoclonal antibody and used to immunize BALB/c mice in a congenital transmission study. NcSRS2 was a highly conserved protein as indicated by comparison of deduced amino acid sequence obtained from NcSRS2 gene sequences of 10 geographically distinct N. caninum isolates. Mice immunized with purified native NcSRS2 produced antigen-specific antibody, primarily of IgG 1 subtype. Following challenge during gestation with 10(7) tachyzoites, immunized mice had a statistically significant decreased frequency of congenital transmission compared to non-immunized mice (P<or=0.05) or mice inoculated with adjuvant alone (P<or=0.01). Decreased congenital transmission among immunized mice correlated with a predominately Th2 immune response compared to non-immunized mice as indicated by an increased ratio of interleukin 4 (IL-4) to interferon gamma (IFN-gamma) secretion from antigen-stimulated splenocytes. The results provide a rationale for NcSRS2 as a candidate subunit vaccine antigen for reduction of N. caninum congenital transmission. Furthermore, the studies suggest that a Th2 immune response, if directed against an appropriate antigen, may induce protection against N. caninum congenital infection in mice.

Animals↗

Therapeutic vaccination in patients with gastrointestinal malignancies. A review of immunological and clinical results.

Gastrointestinal (GI) malignancies are the most common types of human cancers. Despite the introduction of new cytotoxic drugs, a large proportion remains incurable. There is a great need to develop new complementary therapeutic modalities. Strategies exploiting targeted therapies are expanding. The focus of the present article is to review active specific immunotherapy (vaccination) in patients with GI malignancies. The review comprises a description of the immunogenicity of GI malignancies, various types of tumour antigens and mechanisms of action of cancer vaccines. Tumour escape from immune surveillance, vaccine strategies and adjuvants are also described. Clinical and immunological endpoints of cancer immunotherapy are outlined. Results of therapeutic vaccine trials published mainly during the last 5 years in PubMed enrolling a minimum of six patients with GI malignancies are included. Studies presented at the two last annual meetings of the American Society of Clinical Oncology are also covered. More than 2000 patients have been vaccinated with tumour antigens (self antigens). The procedure is safe and no autoimmune disorders have been observed after >4 years follow-up in a substantial number of patients. Humoral and cellular tumour antigen-specific immune responses were induced. A correlation between immune responses and prolonged overall survival was seen in several studies. The most encouraging results were noted in randomised controlled phase II/III trials including over 1300 colorectal carcinoma patients with minimal residual disease. A statistically significantly improved disease-free or overall survival was shown either in all vaccinated or in sub-groups of patients. Promising results were also reported in pancreatic and hepatocellular carcinoma. If the results of the randomised controlled trials hold true, active specific immunotherapy may provide a new promising targeted therapeutic approach in GI malignancies with minimal toxicity. Further enlarged randomised controlled studies are warranted to confirm the results, particularly in colon carcinoma with minimal residual disease.

Antigens, Neoplasm↗

The proliferative properties of tumor cells differentially correlate with the host immune responses in anogenital Bowen's disease.

Bowen's disease is a squamous cell carcinoma in situ that rarely invades into the underlying dermis. In order to evaluate the relationship between the cytological properties of the tumor cells and the host immune response, we have examined the expression of p53 and proliferating cell nuclear antigen (PCNA), and the number of mitotic cells, clumping cells, koilocytes, Langerhans cells (LCs) and dermal lymphoid cell infiltration in 18 cases of anogenital Bowen's disease. When compared with normal anogenital skins (n = 10), a statistically significant number of p53-positive cells, PCNA-positive cells, mitotic cells, clumping cells, koilocytes and dermal lymphoid cells was observed in the cases of Bowen's disease. Importantly, there existed a very strong correlation between the number of PCNA-positive tumor cells and the number of infiltrated dermal lymphoid cells. Moreover, the number of mitotic cells significantly correlated with the number of intratumoral LCs. The in situ hybridization technique for human papilloma virus (HPV) demonstrated that the HPV-infected Bowen's disease showed a similar histological and immunohistological pattern as the HPV-non-infected counterparts, except for increased koilocyte formation and decreased p53 positivity. The present data suggest that the proliferative activity of Bowen's disease significantly correlates with the host immune reaction, and that the host immune system may differentially recognize the different cytological properties of tumor cells in the Bowen's disease.

Adult↗

The susceptibility of mice to immune-mediated neurologic disease correlates with the degree to which their lymphocytes resist the effects of brain-derived gangliosides.

SJL mice develop immune-mediated disorders of the central nervous system (CNS) when infected with certain neurotropic viruses or when immunized with myelin Ags. Other strains including BALB/c are more resistant to these diseases. During Sindbis virus-induced encephalitis, both mice are easily infected and elicit rapid mononuclear cell inflammation in the brain. However, only SJL mice develop immune-mediated paralysis; BALB/c mice remain asymptomatic. To understand how the same stimulus produces such divergent immunologic effects on the host, the present study investigated lymphocytes that were isolated from the brains of Sindbis virus-infected animals. Cells from the brains of SJL mice exhibited more proliferation, produced more IL-2, maintained a higher viability, and expressed less bax mRNA (a proapoptotic mediator) than did lymphocytes from the brains of BALB/c mice. Since the central nervous system is enriched in gangliosides that regulate T cell proliferation and IL-2 production in vitro, purified brain-derived gangliosides were tested on peripheral lymphocytes from both strains. These lipids had less of an effect on the mitogen-induced proliferation, IL-2 production, activation-induced cell death, and up-regulation of bax mRNA in lymphocytes from SJL mice compared with those from BALB/c mice. Thus, gangliosides may inhibit various T cell effector functions and induce T cell apoptosis to a greater degree in the brains of BALB/c mice compared with the brains of SJL mice. This relative deficiency in local lymphocyte regulation may enhance the susceptibility of SJL mice to immune-mediated neurologic disease.

Acute Disease↗

Circulating and deposited immune complexes in patients with glomerular disease: immunopathologic correlations.

The presence of circulating immune complexes (ICs), and alterations of serum immunoglobulins G, A, and M, properdin factor B, and C3 and C4 levels were correlated with glomerular immune deposits in 50 consecutive renal biopsy patients. Urine from 25 of these patients was also examined for ICs. Agarose gel zone electrophoresis (AGE) was used for IC screening. This method detects greater than or equal to 200 ng of IC per 1.5 microliter sample application (approximately equal to 130 micrograms/ml of serum immune complexes) and gives some indication of antigen or antibody excess in the ICs. Glomerular immune deposits were detected by immunofluorescence and electron microscopy in 72% (36/50) of these patients. Circulating and/or urinary IC were found in 69% (25/36) of patients with positive immunofluorescence and 78% (11/14) of patients with negative immunofluorescence. Five of 11 patients with circulating IC but no renal deposition presented with idiopathic crescentic glomerulonephritis (ICGN). These results indicate that IC that persist in the circulation and/or pass renal glomeruli with minimal deposition may result in tissue injury. Circulating IC in antibody excess were detected in all patients with membranous glomerulonephritis. ICs were also found in 55% of patients with IgA nephropathy. Our observations support the hypothesis of an immune complex pathogenesis for these diseases. Determination of circulating and urinary IC in patients with glomerular disease may help in clinical assessment and provide information concerning the pathogenesis of these diseases in humans.

Adolescent↗

Replication and propagation of attenuated vesicular stomatitis virus vectors in vivo: vector spread correlates with induction of immune responses and persistence of genomic RNA.

Live-attenuated vesicular stomatitis virus (VSV) vectors expressing foreign antigens induce potent immune responses and protect against viral diseases in animal models. Highly attenuated (VSV-CT1) or single-cycle VSV (VSVDeltaG) vectors induce immune responses lower than those generated by attenuated wild-type VSV vectors when given intranasally. We show here that reduced spread of the more highly attenuated or single-cycle vectors to other organs, including lymph nodes, correlates with the reduction in the immune responses. A reverse transcription, real-time PCR assay for VSV genomic RNA (gRNA) sequences showed long-term persistence of gRNA from replicating vectors in lymph nodes, long after viral clearance. Such persistence may be important for induction of potent immune responses by VSV vectors.

Animals↗

Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy.

BACKGROUND AND AIMS: Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment. PATIENTS AND METHODS: Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab. RESULTS: Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes' stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment. CONCLUSION: The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes' B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.

Adenocarcinoma↗

Transfer of resistance with syphilitic immune cells: lack of correlation with mitogenic activity.

Hamsters infected intradermally with Treponema pallidum Bosnia A develop extensive chronic skin lesions, usually accompanied by metastatic lesions involving the paws, lips, and anal region and by lymph nodes teeming with treponemes. Throughout the course of syphilitic infection, cells from the inguinal lymph nodes responded poorly to stimulation with suboptimal, optimal, or supraoptimal concentrations of concanavalin A, phytohemagglutinin P, or lipopolysaccharide. The response of syphilitic spleen cells was variable. Depression of lymphocyte reactivity to mitogens preceded clinical signs of infection and correlated well with the chronicity of syphilitic infection. When syphilitic hamsters were treated with a curative dose of penicillin, their mitogenic responses returned to normal or were slightly elevated. No correlation existed between mitogenic activity and the ability of lymphoid cells to induce an effective immune response when transferred to normal recipients. No significant differences in protection were detected among recipients of immune cells with or without activity to mitogens. These results demonstrate that lymphocyte transformation by mitogens in vitro is not a measure of effective treponemicidal activity and so may not be a valid indicator of the protective immune status of syphilitic animals.

Animals↗

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity.

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.

Acute Disease↗

Production of interleukin-6, tumor necrosis factor alpha and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients.

In patients with chronic renal failure alterations in monokine production are a common feature. Their clinical relevance has not yet been proven. We show here a correlation between an overproduction of interleukin-(IL)-6 and tumor necrosis factor alpha (TNF alpha) upon stimulation with LPS by mononuclear cells in vitro and the clinical grade of immunodeficiency found in these patients. Higher levels of IL-6 and TNF alpha were correlated with an immunocompromized state, that is, non-responsiveness to hepatitis B vaccination, whereas patients with a better immune competence showed the same levels of these cytokines as healthy controls. Only the patients with a good immune function showed a high secretion of IL-10. The feedback mechanism of IL-10 for reducing monokine synthesis seems to be intact in these patients. Thus the secretion of IL-10 might be regarded as a compensatory mechanism which controls monokine induction by chronic renal failure and hemodialysis treatment. Immunocompromized patients who are unresponsive to hepatitis B vaccination seem to be unable to enhance IL-10 synthesis for control of monokine overproduction. This results in higher levels of IL-6 and TNF alpha that might be involved in the pathogenesis of reduced immune defense.

Antibodies, Monoclonal↗

Immunologic evaluation and prognosis in patients with head and neck cancer.

Patients with mucosal squamous cell carcinoma of the head and neck generally have suppressed T cell function, and this suppression tends to be more pronounced with progression of disease. The prognostic relationships of multiple tests of immune function were analyzed in 183 clinically staged patients. Correlation of immune parameters with prognosis was evident only with the DNCB response, which correlated with recurrence in stages I and II disease (but not in stages III and IV). There was no correlation of any of the in vitro tests of immunofunction with recurrence in any stage. There were no correlations between any of the immune parameters and age or sex nor between DNCB reactivity and any of the in vitro responses.

Carcinoma, Squamous Cell↗

Circulating immune complexes in cystic fibrosis and their correlation to clinical parameters.

Circulating immune complexes (CIC) have been found to be elevated in individuals with cystic fibrosis (CF). Previous investigators, using a variety of assays, have reported high levels of CIC in as many as 86% of these patients. Our study followed the progress of 25 patients with CF over a period of 10 months to determine which, if any, clinical parameters correlated with the occurrence and/or concentration of CIC. Immune complex determinations were performed using a coprecipitation method with equine rheumatoid-complement complex. One hundred percent of the CF patients had CIC elevated above normal levels, however, levels of CIC did not correlate with the severity of an individual's acute exacerbation. Clinical parameters including pulmonary function tests, vital signs, total serum IgG levels, and other laboratory studies, were obtained on each individual and analyzed with respect to their relationship to CIC. Only four of 38 parameters examined had p less than 0.05. Factors that showed significant correlation to elevated CIC's in the highly elevated portion of our CIC population were poor NIH score, increased patient age, low peak expiratory flow rate, and elevated total serum IgG. These clinical values are associated more with the measurement of chronic disease. These data suggest that CICs cannot be used as an indication of short-term prognosis or as a monitor to follow the course of acute severe lung infections in the CF patient. Of interest was the observation that all patients who died during the course of the investigation had CIC levels greater than 80 micrograms/ml.

Adolescent↗

Correlates of Leishmania-specific immunity in the clinical spectrum of infection with Leishmania chagasi.

Patients from across the spectrum of clinical manifestations of Leishmania chagasi infection were evaluated for in vitro correlates of immunity. Peripheral blood mononuclear cells were assayed for parasite-specific lymphoproliferation, cytokine generation, and the capacity to activate autologous macrophages to kill intracellular amastigotes. Patients with acute kala-azar were generally unreactive in each of these assays. Children with subclinical infection demonstrated relatively low levels of proliferation and interferon-gamma production, but none went on to develop overt kala-azar during the study. Patients evaluated after therapy for kala-azar demonstrated yet higher levels of lymphoproliferation and cytokine generation and produced low but significant levels of cytokines in vitro in response to parasite antigens, but not during the activation of infected macrophages. Finally, peripheral blood mononuclear cells from adults with positive delayed-type hypersensitivity responses and no history of kala-azar showed the broadest reactivity in vitro. These patients' cells generated the largest amounts of activating cytokines in vitro during the activation of autologous macrophages to a leishmanicidal state.

Acute Disease↗

ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.

Humans↗