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The object of the present work was to investigate: a) The cytotoxic activity of cytophilic antibody in sera from guinea pigs sensitized with the testicular antigen; b) The presence of immune complexes. In vitro cytotoxicity induced by hyperimmune sera or by the cytophilic antibodies eluted from the corresponding macrophages, was demonstrated after incubation with either germinal cells or spermatozoa. Marked cytotoxicity was also observed in vivo when sera or antibodies were injected into the tests, as shown by sequential histologic studies. Circulating immune complexes, as tested by the 125I-C1q binding assay, were not detected in these sera. On the contrary, high levels of circulating immune complexes were found when the polyethyleneglycol precipitation test was used. It can be concluded that the cytotoxic effect induced by cytophilic antibodies of IgG2 nature, may be associated with polyethyleneglycol precipitating immune complexes.
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Sixty-eight per cent of a consecutive series of 65 renal biopsies showed immune deposits in extraglomerular blood vessels. Although they occurred with a variety of clinical disorders and histological diagnoses, they were associated in particular with an acute nephritic syndrome, focal proliferative glomerulonephritis and non-specific mesangial changes. IgM was the commonest immunoglobulin class to be deposited and higher levels of IgM-containing complexes were detected in the serum of those patients with vascular deposits. Hitherto, immunofluorescent studies of renal biopsies have concentrated mostly on glomeruli but this study suggests that the extraglomerular vasculature deserves closer attention. The mechanisms for this pattern of localization are discussed.
To determine whether xanthenone acetic acid (XAA) analogues of flavone acetic acid (FAA) have similar ischemic and nonischemic mechanisms of antitumor action to FAA, a series of such compounds was evaluated in vivo and in vitro. Necrotising activity and changes in tumor blood flow were measured in Colon 38 tumors, and morphological changes assessed in immune cell-infiltrated EMT6 tumor cell spheroids, after treatment with FAA, XAA and its derivatives (5-methyl XAA, 5,6-dimethyl XAA, 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid). FAA, XAA and the 5-methyl and 5,6-dimethyl analogues of XAA were active in inducing tumor necrosis, falls in tumor perfusion and characteristic morphological changes in multicellular spheroids. The other XAA analogues lacked these activities. 5-methyl XAA and 5,6-dimethyl XAA were more potent than FAA or XAA. The results suggest that XAA and its analogues have the same mechanisms of action as FAA, and that both the vascular and the immune effects of these compounds are mediated via a common biochemical receptor.
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The nature of the systemic immunity induced by various vaccines against fowl cholera disease in turkeys was investigated. Used as vaccines were three avirulent strains (CU, M2283, and P1580) of Pasteurella multocida administered in the drinking water and a bacterin administered parenterally. A passive hemagglutination test was developed to measure levels of systemic humoral immunity. Systemic cell-mediated immune response was assayed by an in vitro immunostimulation microculture system utilizing peripheral blood lymphocytes. The bacterin induced high levels of systemic humoral and cell-mediated immune responses which respectively persisted for 8 and 6 weeks. The CU strain of live vaccine induced average levels of systemic immunity (humoral and cell-mediated) which respectively persisted for 4 and 6 weeks. The M2283 strain of live vaccine also induced average levels of systemic immunity (less than induced by the CU strain) which respectively persisted for 4 and 6 weeks. The P1580 strain of live vaccine induced low levels of systemic immunity which persisted for only 2 weeks. Results from data generated from an analysis of correlation between levels of immunity and protection indicate that systemic immunity (humoral and cell-mediated) played a significant role.
Gene networks of protective lymphocytes after immune activation with live attenuated vaccines remain poorly characterized. Because Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine can confer protection against fatal forms of tuberculosis in humans and monkeys, we made use of macaque models to optimally study immune gene networks after BCG vaccination/infection. We first established and validated a large-scale real-time quantitation system and then used it to measure expression levels of 138 immune genes after BCG vaccination/infection of rhesus macaques. Systemic BCG vaccination induced up to 600-fold increases in expression of 78 immune genes among the 138 genes tested at the time when BCG-elicited T cell responses and immunity were apparent. These up-regulated transcripts constituted multiple gene networks that were linked to various aspects of immune function. Surprisingly, the up-regulation of most of these immune genes in the gene networks occurred at 1 week and was sustained at > or = 6 weeks after BCG vaccination/infection. Although early activation of immune gene networks was an immune correlate of anti-BCG immunity, prolonged up-regulation of these networks coincided with the development of vaccine-elicited T cell responses after BCG vaccination/infection. These findings provide molecular evidence suggesting that the BCG-induced gene networks may represent global transcriptomes and proteomes underlying the development of T cell responses and, ultimately, immunity to mycobacteria.
We investigated the cytokine profile of cells of the innate immune response and its association with active (ACT), asymptomatic (AS) and cured (CUR) human visceral leishmaniasis (VL), as well as noninfected (NI) subjects. The frequency of cytokine-producing cells was determined after short-term in vitro incubation of whole peripheral blood samples with soluble Leishmania antigen (SLA). Our data demonstrated a predominant type 2 cytokine profile in NI and ACT. In NI, we observed an increase of IL-4+ neutrophils, IL-10+ eosinophils besides a decrease of tumour necrosis factor (TNF)-alpha+ eosinophils/monocytes. Yet in ACT, we observed an increase of IL-4+ neutrophils and natural killer (NK) cells and IL-10+ monocytes, a reduced frequency of IL-12+ and IFN-gamma+ eosinophils and lower levels of TNF-alpha+ and IL-12+ monocytes. AS presented a mixed profile, characterized by an increase of IFN-gamma+ neutrophils/eosinophils and NK cells, of IL-12+ eosinophils/monocytes, as well as increase of IL-4+ neutrophils and NK cells and IL-10+ eosinophils/monocytes. In contrast, CUR was characterized by a type 1 response with an increase of IFN-gamma+ neutrophils/eosinophils and NK cells, associated with an increase in IL-12+ monocytes. In conclusion, we show a correlation between innate immune cytokine patterns and clinical status of VL, suggesting that these cells, in addition to other factors, may contribute to the cytokine microenvironment in which Leishmania-specific T cells are primed and to disease outcome.
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Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.
BACKGROUND: Despite multiple, repeated exposures to HIV-1, some individuals never seroconvert. Mucosal and systemic immune correlates of this condition have been analysed in HIV-1-exposed women but no data are available concerning mucosal immunity and HIV-1-specific immune responses in exposed but uninfected men. DESIGN: We analysed cellular and humoral immune parameters in peripheral lymphocytes, seminal fluid and urethral swabs of 14 recently HIV-1-exposed seonegative (ESN) heterosexual men, seven HIV-seropositive patients and seven healthy controls. RESULTS: HIV-1-specific IgA were detected in urethral swabs of 11 out of 14 ESN and of six out of seven HIV-seropositive patients; Env- and Gag-specific IFNgamma-producing CD4 and CD8 peripheral lymphocytes were present in ESN and HIV-seropositive patients; seminal lymphocytes, but not peripheral blood lymphocytes, of ESN were enriched in activated populations (CD8CD38RO and CD4CD25). p24-specific cytotoxic T lymphocytes were correlated with the percentage of CD4 in the HIV-seropositive partners. High urethral concentrations of HIV-1-specific IgA were seen in those ESN with the most recent unprotected sexual episode. CONCLUSIONS: This is the first report of HIV-specific mucosal immunity in ESN men. These data add to the body of knowledge of the immune correlates present in exposed, uninfected individuals and might be important in vaccine design.
INTRODUCTION: Cholesterol homeostasis has been identified as an essential downstream pathway of mutations in TP53. Esophageal cancer is one of the most prevalent malignancies exhibiting the mutation. OBJECTIVES: To explore the significance of cholesterol metabolism-related characteristics in tumor phenotype and treatment outcomes of esophageal cancer. METHODS: We established a cholesterol metabolism-related gene set (CMGs) and performed Lasso-Cox analysis to identify prognostic signatures. Nomogram-based risk scores and clinical stages afterwards were constructed and evaluated. We simultaneously identified two metabolic subtypes based on the distinct features of the CMGs. We annotated the functional and pathway characteristics of differentially expressed genes between the clusters and compared the differences in clinical and immune characteristics. Finally, we assessed the prognostic value of signatures in the GSE53625 and two clinical cohorts using whole-exon sequencing and multiplex immunofluorescence. RESULTS: Our study identified five cholesterol prognosis-related genes (CRGs) that demonstrated superior prognostic efficacy in the training set compared to clinical staging, validated in independent public databases and two clinical cohorts. According to the different expression patterns of the signatures, patients were divided into two subtypes. The C1 group demonstrated poorer overall survival, response to immunotherapy, and downregulation of the p53 pathway. In the immune correlation analysis, we found that the risk score based on 5-signature model was significantly positively correlated with the abundance of suppressive immune cells and the immune checkpoints. Finally, we explored the impact of expression and genomic polymorphism of the signatures on the prognosis at the pan-cancer level. CONCLUSIONS: Our findings underscore the distinct expression patterns of CRGs in esophageal cancer. These signatures are efficient to serve as prognostic indicators and assess the effectiveness of immunotherapy. They may also represent promising targets in other TP53 mutant malignancies.