Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.     

结节病5例的诊断

本文报告了5例结节病的临床、X线、CT表现,追踪了疾病的转归,重点描述了重型系统性结节病,提醒临床医师予以重视。     

Psychological Correlates of Nonspecific Skin Conductance Responses

Previous research has indicated that the frequency of skin conductance responses without external stimulation or motor activity is a reliable indicator of psychophysiological states and traits. Some authors have suggested that cognitions elicit nonspecific skin conductance responses. These cognitions may resemble the stimuli that evoke a specific skin conductance response. In a within subjects design (n = 31 graduate students) the onset of nonspecific skin conductance responses triggered a signal for the subject to rate cognitions on several indices. These ratings ("absent" to "fully present") were compared with samples in the absence of phasic electrodermal activity. The subjects' current concerns, negative emotion, subjective arousal, and inner speech were rated to be significantly more intense at the time of nonspecific skin conductance responses compared to electrodermal nonresponding periods. Cognitive processes seem to be concomitants of nonspecific skin conductance responses.     

Alterations in Nonspecific Cross-reacting Antigen Localization during Cell Culture

Nonspecific cross reacting antigen (NCA), a constituent of the carcinoembryonic antigen family, was localized ultra-structurally in a human lung adenocarcinoma cell line, PC 9. NCA was distributed predominantly on the plasma membrane in the early phases of cell culture. Deletion of fetal bovine serum (FBS) from the culture medium suppressed cell division without significantly altering cell viability, and induced a dramatic but reversible change in NCA localization. Under these conditions, NCA was localized to membrane degradation products within cytoplasmic vesicles and vacuoles. Acid phosphatase activity was also present in some of these intracellular structures. Similar changes in NCA localization were seen in cells cultured with FBS at day 6 when the cells reached a plateau stage of growth. These findings strongly suggest that plasma membrane degradation is accelerated by the cessation of cell growth. Cytoplasmic reactivity for NCA in cancer cells may therefore reflect degradation of plasma membrane-associated NCA and may not necessarily be correlated with increased systhesis of this glycoprotein. Acta Pathol Jpn 39: 772 778, 1989.     

Study on nonspecific immunity in pregnant women: II. Effect of hormones on chemiluminescence response of peripheral blood phagocytes.

To analyze the mechanisms of increased nonspecific immunity in pregnant women, the effect of various hormones on the phagocytic activity was estimated by a luminol-dependent chemiluminescence (CL) response during phagocytosing opsonized zymosan. The CL response of whole blood supplemented with exogenous human chorionic gonadotropin (hCG) increased significantly in all the male and female subjects and pregnant women. An approximate two- to fourfold increase was observed in comparison with the unsupplemented control in each subject at concentrations ranging from 1 to 1,000 IU/ml after 48 h of incubation (P less than 0.05). Progesterone slightly stimulated the CL response in female subjects only, but had no effect on male and pregnant women. Estradiol (E2) did not stimulate the CL response in any subject. The expression of Fc and C3b receptors on the surface of polymorphonuclear leucocytes (PMNL) in pregnant women was also investigated by measuring the immunofluorescence stained with monoclonal antibody to Fc and C3b receptors, respectively. The relative numbers of Fc receptors increased significantly in the third trimester compared to those of female control (P less than 0.05). Those of C3b receptor also increased in the second and third trimester (P less than 0.005). These results suggested that the nonspecific immunity represented by phagocytic activity in pregnant women increased with both oxidative metabolic responsiveness and the expression of membrane receptors. Besides, the increased phagocytic activity of the maternal host is probably due to the stimulatory effect of both endogenous and exogenous hCG on their peripheral blood phagocytes.     

Contraluminal transport of small aliphatic carboxylates in the proximal tubule of the rat kidney in situ

In order to study the characteristic of contraluminal transport of hydrophylic small fatty acids the in situ stopped flow microperfusion technique [12] has been applied. By measuring with 4 s contact time the decrease in the contraluminal concentration of the respective radiolabelled substances the concentration dependence of the influx into the cortical cells was tested. The 4 s decrease in contraluminal concentration of chloroacetate,l-lactate,d-lactate, 3-hydroxybutyrate and acetoacetate was between 26% and 31%. For each substance the percent decrease was the same, no matter whether it was offered in a concentration of 0.1 or 10 mmol/l. Contraluminal disappearance of 0.1 mmol/ll-lactate was not influenced by 5 mmol/l H₂DIDS, probenecid, phloretin, mersalyl or cyanocinnamate, but it was significantly (37%) inhibited by 5-nitro-2-(phenyl-propyl-amino) benzoate, a blocker of the nonspecific anion channel. The percent decrease in propionate uptake was somewhat larger — between 36% and 39% — but again not different at 0.01, 0.1, 1.0 and 10 mmol/l. With pyruvate the contraluminal decrease was 20% at 0.1 mmol/l and 31% at 10 mmol/l. The percent disappearance of the aromatic pyrazinoate was 38% and 34% at 0.1 and 10 mmol/l and for nicotinate 42% and 22%, respectively. The disappearance of nicotinate (0.1 mmol/l) was significantly inhibited by 10 mmol/l pyrazinoate and paraaminohippurate (PAH). The data are in agreement with the hypothesis that the hydrophilic small fatty acids traverse the contraluminal cell side by simple diffusion, possibly via the unspecific anion channel [14], pyruvate via the dicarboxylic acid pathway in a cooperative manner and pyrazinoate, as well as nicotinate, via the PAH pathway.     

Molecular characterization of a novel pattern recognition protein from nonspecific cytotoxic cells: sequence analysis, phylogenetic comparisons and anti-microbial activity of a recombinant homologue

Nonspecific cytotoxic cells (NCC) are the first identified and most extensively studied killer cell population in teleosts. NCC kill a wide variety of target cells including tumor cells, virally transformed cells and protozoan parasites. The present study identified a novel evolutionarily conserved oligodeoxynucleotide (ODN) binding membrane protein expressed by channel catfish (Ictalurus punctatus) NCC. Peptide fingerprinting analysis of the ODN binding protein (referred to as NCC cationic anti-microbial protein-1/ncamp-1) identified a peptide that was used to design degenerate primers. A catfish NCC cDNA library was used as template with these primers and the PCR-amplified product was sequenced. The translated sequence contained 203 amino acids (molecular mass of 22,064.63 Da) with characteristic lysine rich regions and a pI=pH 10.75. Sequence comparisons of this protein indicated similarity to zebrafish (51.2%) histone family member 1-X and (to a lesser extent) to trout H1. A search of EST databases confirmed that ncamp-1 is also expressed in various tissues of channel catfish as well as zebrafish. Inspection for signature repeats in ncamp-1 and comparisons with histone-like peptides from different species indicated the presence of multiple lysine based motifs composed of AKKA or PKK repeats. The novel protein was cloned, expressed in E. coli and the recombinant was used to generate rabbit anti-serum. The recombinant ncamp-1 bound GpC and CpG ODNs and was detected with homologous anti-ncamp-1 polyclonal antibodies. Western blots of NCC membranes using anti-ncamp-1 serum detected a 29 kDa protein. Binding competition experiments demonstrated that anti-ncamp-1 antibodies and GpC bound to the same protein on NCC. Two different truncated forms of ncamp-1 as well as the full-length recombinant protein exhibited anti-microbial activity. The present study demonstrated the expression by NCC of a new membrane protein that may participate in the recognition of bacterial DNA and as such participate in innate anti-microbial immune responses in teleosts.     

Bronchoconstriction of the asthmatic airway by inhaled and ingested propranolol

Summary Responsiveness to inhaled histamine and DL propranolol hydrochloride was measured in 31 adult asthmatics and compared with bronchoconstriction provoked by acute oral propranolol dosing (max 160 mg).Twelve asthmatics developed 15% reduction in the forced expired volume in 1 s (FEV₁), 2 h after 100 mg oral propranolol; cardiac -adrenoceptor blockade was confirmed by cycle exercise tests in the 19 without airway response. The provocative inhaled dose of each aerosol causing a 20% fall in FEV₁ (PC₂₀) was lower, histamine 0.43 mg·ml^–1, propranolol 3.12 mg·ml^–1, in the 12 with a positive oral test compared with the 19 with a negative test, PC₂₀ histamine 1.65 mg·ml^–1, PC₂₀ propranolol 16.2 mg·ml^–1 (P < 0.001 for both aerosols). A correlation was demonstrated between the PC₂₀ values for asthmatics with a negative oral test (r=0.72, P < 0.001, n=19) but not for the remainder (r=0.14, P > 0.05, n=12).Plasma propranolol concentrations (CL, ng·ml^–1) after the final oral dose did not correlate with the % FEV₁(26.3) (r=-0.28) when an airway response was provoked or with the reduction in exercise tachycardia (25.9%) (r=0.31) when no bronchoconstriction occurred. CL exceeded the limit of detection after the final inhaled propranolol dose (7.5 ng·ml^–1) and was weakly related to the PC₂₀ propranolol value (r=0.53, P=0.01, n=27). The prevalence of a positive oral challenge was low in this group (39%). APC₂₀ propranolol value which was 100% sensitive as a predictor of a positive oral test had low specificity (58%) and a low predictive value (60%).This study has not found that nonspecific bronchial responsiveness to histamine or specific responsiveness to inhaled propranolol can be employed to predict bronchoconstriction in asthmatics following acute oral propranolol dosing.     

Effect of biphenyl dimethyl dicarboxylate on the cellular and nonspecific immunosuppressions by ketoconazole in mice

The effect of biphenyl dimethyl dicarboxylate (PMC) on the cellular and nonspecific immunosuppressions by ketoconazole (KCZ) was investigated in ICR mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14 consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered at 160 mg/kg/day 2 hrs after the administration of PMC. Immune responses of the delayed-type hypersensitivity (DTH) reaction to sheep red blood cells (SRBC), phagocytic activity and natural killer (NK) cell activity were evaluated. DTH reaction to SRBC was enhanced to normal level by the combination of PMC and KCZ, compared with treatment of KCZ alone. In the combination of PMC and KCZ, as compared with the treatment of KCZ alone, there were also significant increases in activities of natural killer (NK) cells and phagocytes along with circulating leukocytes. These findings indicate that PMC shows a significant restoration from the immunotoxic status induced by KCZ.     

Nonspecific interstitial pneumonia

Traditionally, a subset of patients diagnosed as having idiopathic pulmonary fibrosis had positive results on cellular biopsies (prominent lymphoplasmacytic inflammation), bronchoalveolar lavage lymphocytosis, a clinical response to steroids, and a better long-term prognosis. On review of the lung histopathology, the lesion was characterized by varying degrees of inflammation and fibrosis. This entity is now recognized as a distinct entity among idiopathic interstitial pneumonias.