Younger age groups account for proportionally more mortality in influenza pandemics than in seasonal influenza epidemics. Mechanisms that might explain this include young people suffering from an over-reactive immune system ("cytokine storm"), older people benefiting from cross-immunity from a wider variety of previous influenza infections ("antigenic history"), and lifetime immune responses in all people being shaped by their first influenza A infection ("antigenic imprinting" or "original antigenic sin"). We examined whether these mechanisms can explain age-specific influenza mortality patterns, using the complete database of individual deaths in Canada from 1951 to 1999. The mortality pattern during the 1957 pandemic indicates that antigenic imprinting plays an important role in determining age-specific influenza virulence and that both shift years and major drift years contribute significantly to antigenic imprints. This information should help pandemic planners to identify age groups that might respond differently to novel influenza strains.
Lymphocyte functions are dependent on fatty acid composition of membranes, and impaired functions can predispose patients to infection after burn injury. The current study was designed to describe changes in lymphocyte-phospholipid composition and lymphocyte-related immune functions from early to late recovery time points after burn injury.
Firefighter's Burn Treatment Center, University of Alberta Hospital, Edmonton, Alberta, Canada.
Subjects (n = 10) with >10% total body surface burn area.
Blood was drawn from subjects at specific time points (0 days to >50 days) after burn injury. Fatty acid composition of the major phospholipid classes of isolated lymphocytes was determined by using gas liquid chromatography. Lymphocyte phenotypes and proliferation ([(3)H]-thymidine uptake and interleukin-2 and interferon-gamma production) in response to mitogens were determined. Lymphocyte phospholipid 20:4n-6 content was 30% to 60% lower early compared with late postburn time points (p
Chuvash polycythemia results from a homozygous 598C>T mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1alpha and HIF-2alpha causing altered expression of HIF-1 and HIF-2 inducible genes. As hypoxia induces expression of pro-inflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. We analyzed plasma concentrations of Th1 (interleukins-2 and 12, interferon-gamma, granulocyte-monocyte colony-stimulating factor, tumor necrosis factor-alpha) and Th2 cytokines (interleukins-4, 5, 10, and 13) using the Bio-Plex multiplex suspension array system in 34 VHL598C>T homozygotes and 32 VHL wild-type participants from Chuvashia. Concentrations of all the Th1 and Th2 cytokines measured were elevated in the VHL598C>T homozygotes compared with the control wild-type participants, but the ratios of Th1 to Th2 cytokines did not differ by genotype. In parallel, peripheral blood concentrations of CD4 positive T-helper cells and CD4/CD8 ratio were lower in the VHL598C>T homozygotes. In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved.
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Brown Norway rats are widely used as a model of asthma, whereas Sprague Dawley rats do not develop allergic reactions under the same conditions. Given the importance of alveolar macrophages (AM) in down-regulating cellular immune responses in the lung, we postulated that the different susceptibilities in the development of airway allergic reactions in these rat strains may be related to functional differences in their AM. We investigated the production of important mediators in asthma, namely tumour necrosis factor (TNF), interleukin-10 (IL-10), IL-12, IL-13, nitric oxide (NO) and macrophage inflammatory protein-1alpha (MIP-1alpha), by AM of unsensitized Sprague Dawley and Brown Norway rats. AM were purified by adherence and stimulated with OX8 (anti-CD8 antibody) or LPS. OX8 stimulation significantly increased the release of TNF, IL-10 and NO in both strains of rats, whereas MIP-1alpha and IL-12 release were increased in Brown Norway rats only. Interestingly, stimulated AM from Sprague Dawley rats released significantly more TNF and less IL-10, IL-12, IL-13, MIP-1alpha and NO compared with AM from Brown Norway rats. These differences were also observed at the mRNA level, except for TNF. Thus, AM from Brown Norway and Sprague Dawley rats are functionally different. Furthermore, LPS- and OX8-stimulated AM from Brown Norway rats produce more Th2 type cytokines (IL-10 and IL-13) than AM from Sprague Dawley rats, suggesting that these cells may play an important role in creating a cytokine milieu that may favour the development of allergic reactions.
BACKGROUND: Atopic children show increased expression and production of the Th2-associated cytokines IL-4, IL-5, IL-13, and IL-9 from PBMCs after stimulation with allergen, but it has previously not been clearly determined whether the Th2-cytokine production is restricted to the inhalant allergen the child is sensitized to, and whether perennial or seasonal allergens induce different cytokine responses. Our purpose was to determine whether in vitro Th2 cytokine production is specific to the sensitizing allergen, and to compare the cytokine responses to a perennial and a seasonal allergen in monosensitized and polysensitized children. METHODS: Using semiquantitative RT-PCR, we analyzed the expression of the cytokines IL-4, IL-5, IL-13, IL-9, IL-10, and IFN-gamma after stimulation of PBMCs with house-dust-mite (HDM) or ryegrass allergen. The cells were sampled from groups of 6-year-old children sensitized to either HDM (n=20) or ryegrass (n=24), or to both allergens (n=20), as well as from a nonatopic group (n=20). RESULTS: After stimulation with HDM allergen, PBMCs from children sensitized only to HDM expressed increased mRNA levels of the Th2 cytokines, but not of IL-10 and IFN-gamma, whereas ryegrass stimulation did not result in increased cytokine expression. PBMCs from children sensitized to HDM and ryegrass expressed increased Th2 cytokines after stimulation with either of the two allergens. In contrast, PBMCs from children sensitized only to ryegrass did not express increased levels after stimulation with either of the allergens. CONCLUSIONS: The expression of Th2 cytokines after in vitro stimulation of PBMCs from atopic children is specific to the sensitizing allergen, indicating that atopic status per se does not affect the type of T-cell response. In addition, T cells specific to seasonal allergens circulate in the blood out of season only if the child is concomitantly sensitized to a perennial allergen.
Macrophages attack and kill pathologically changed, transformed and tumor cells. However, in some cases they may also support tumor growth, modulate the action of anticancer drugs, and even facilitate the development of drug resistance in tumor cells. Here we present data that bystander fibroblasts NIH3T3 were not only resistant to murine macrophages J774.2 but also blocked their killing action towards murine transformed fibroblasts L929. Macrophages were isolated from mixed cultures by means of CD11b specific immunomagnetic beads, and changes induced by their former co-culturing were studied using DNA microarray technology and other tests. An expression of candidate genes coding for cytokines and for signal transduction pathway proteins was estimated in macrophages in different variants of their co-culture with target cells. Changes in expression of mRNA for interleukin 1beta, NFkappaB, IkappaBalpha, gadd45, and CD5 were detected as the most prominent in the macrophages co-cultured with the transformed cells. Bystander NIH3T3 fibroblasts abolished these changes in the macrophages J774.2, and the level of expression of the above mentioned genes was close to the level seen in the macrophages which did not exert cytotoxicity towards the target fibroblasts. Potential implications and research perspectives of using the macrophage-target cell co-cultures with different bystander cellular partners are discussed.
BACKGROUND: The function of CD8+ T-cell subsets in mediating late allergic responses is incompletely understood. OBJECTIVE: We sought to test the hypothesis that CD8+ alphabeta T cells are proinflammatory in the airways in vivo by using a well-characterized animal model and the technique of adoptive transfer. METHODS: Brown Norway rats were administered CD8 + alphabeta T cells (10 6 ) intraperitoneally purified from lymph node cells of either naive or ovalbumin (OVA)-sensitized rats and were challenged with aerosolized OVA 2 days later. Control rats were sensitized to 100 mug of OVA in Al(OH) 3 subcutaneously or sham sensitized to saline and were OVA challenged 2 weeks later. RESULTS: The OVA-sensitized and OVA-challenged group and the recipients of OVA-primed CD8+ alphabeta T cells had significant late airway responses calculated from lung resistance measured for an 8-hour period after challenge compared with the naive CD8 + alphabeta T cell-transferred group and the sham-sensitized control group. The number of eosinophils in bronchoalveolar lavage fluid increased in the OVA-sensitized group and the OVA-primed CD8+ alphabeta T-cell recipients compared with numbers in the naive CD8+ alphabeta T-cell recipients and the sham-sensitized control group. IL-4 and IL-5 cytokine mRNA expression in bronchoalveolar lavage fluid increased in the OVA-sensitized group and the OVA-primed CD8+ alphabeta T-cell recipients compared with that in the sham-sensitized group. CONCLUSION: We conclude that antigen-primed CD8 + alphabeta T cells might have a proinflammatory role in allergen-driven airway responses in the rat.
To test the hypothesis that CD8+ T cells may suppress the allergen-induced late airway response (LAR) and airway eosinophilia, we examined the effect of administration of Ag-primed CD8+ T cells on allergic airway responses, bronchoalveolar lavage (BAL) leukocytes, and mRNA expression for cytokines (IL-4, IL-5, and IFN-gamma) in OVA-sensitized Brown Norway rats. On day 12 postsensitization to OVA, test rats were administered 2 million CD8+ T cells i.p. isolated from either the cervical lymph nodes (LN group; n = 8) or the spleen (Spl group; n = 6) of sensitized donors. On day 14, test rats were challenged with aerosolized OVA. Control rats were administered PBS i.p. on day 12, and challenged with OVA (n = 10) or BSA (n = 6) on day 14. The lung resistance was measured for 8 h after challenge. BAL was performed at 8 h. Cytospin slides of BAL were analyzed for major basic protein by immunostaining and for cytokine mRNA by in situ hybridization. The LAR was significantly less in the LN group (1.8 +/- 0.5 U; p
BACKGROUND: Cytokines are intercellular polypeptide messengers that mediate immune and inflammatory responses. The temporal profile of interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemotactic protein 1 (MCP-1) expression was examined in anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN). EXPERIMENTAL DESIGN: TIN was induced by immunization of Brown Norway rats with bovine cortical TBM, whereas control rats received ovalbumin. Whole kidney RNA was assessed with the RNase protection assay 3, 7, 8, 9, 10, 12, and 14 days after immunization. Cytokine mRNA expression was correlated with TNF-alpha bioactivity, renal intercellular adhesion molecule-1 expression, and CD18-positive leukocyte infiltration by immunohistochemistry. RESULTS: Increased IL-1 beta, TNF-alpha, and MCP-1 mRNA relative to glyceraldehyde-3-phosphate dehydrogenase appeared on day 7 when TIN involved 10 to 40% of the cortex, and peaked rapidly on day 8 when there was 60 to 80% cortical involvement (at which time 75 to 80% of the infiltrating cells were neutrophils). The increase in TNF-alpha mRNA correlated with increased bioactivity. The influx of mononuclear cells on day 8 was preceded by the expression of MCP-1 mRNA. The infiltrating leukocytes expressed the leukocyte beta 2-integrin (CD18) and were found in areas with increased intercellular adhesion molecule-1 expression. The mRNAs for IL-1 beta, TNF-alpha, and MCP-1 were undetectable by day 10 (at which time 95% of the infiltrating cells were mononuclear). An increase in IL-1 receptor antagonist mRNA paralleled those of IL-1 beta. The expression of IL-6 mRNA was similar to that for IL-1, except that it disappeared by day 9. CONCLUSIONS: There is a temporal association in the expression of IL-1 beta, TNF alpha, MCP-1, and IL-6 with the upregulation of intercellular adhesion molecule-1 and leukocyte infiltration within the tubulointerstitium in anti-TBM antibody-associated TIN. The narrow window of time through which these cytokines are expressed and the coincidence of their peak expression on day 8 suggest complex cytokine interactions in the pathogenesis of anti-TBM antibody TIN.
The inflammatory response induced by the conditioning regime may be related to the outcome in allogeneic stem-cell transplantation (SCT). However, previous statements concerning the prognostic significance of cytokine measurements during conditioning have not been conclusive. We investigated a broad range of cytokines in plasma samples drawn daily immediately before start of pretransplant conditioning and during the conditioning. The presented data indicate that single-day measurements of inflammatory cytokines during conditioning may lead to unreliable conclusions concerning their prognostic significance. However, serial quantitation of soluble tumour necrosis factor receptor I (sTNFRI) is more likely to reflect the degree of inflammatory activation induced by pretransplant conditioning.