An imbalance in mucosal cytokine profile causes transient intestinal inflammation following an animal's first exposure to faecal bacteria and antigens

Intestinal microflora play a critical role in the initiation and perpetuation of chronic inflammatory bowel diseases. In genetically susceptible hosts, bacterial colonization results in rapid‐onset chronic intestinal inflammation. Nevertheless, the intestinal and systemic immune response to faecal bacteria and antigen exposure into a sterile intestinal lumen of a post‐weaned animal with a mature immune system are not understood clearly. This study examined the effects of faecal bacteria and antigen exposure on the intestinal mucosal and systemic immune system in healthy axenic mice. Axenic wild‐type mice were inoculated orally with a crude faecal slurry solution derived from conventionally raised mice and were analysed prior to and then at days 3, 7, 14 and 28 post‐treatment. Ingestion of faecal slurry resulted in a transient, early onset of proinflammatory interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐17 response that was maximal at day 3. In contrast, the transient release of the anti‐inflammatory cytokines IL‐10 and IL‐4 occurred later and was maximal at day 7. Both responses subsided by day 14. This early cytokine imbalance was associated with a brief rise in colonic and caecal histopathological injury score at day 7. The bacterial antigen‐specific systemic response was found to follow the intestinal immune response with a maximal release of both pro‐ and anti‐inflammatory cytokines at day 7. Thus, first exposure of healthy axenic wild‐type mice to normal faecal flora and antigens results in an early proinflammatory cytokine response and transient colonic inflammation that then resolves in conjunction with a subsequent anti‐inflammatory cytokine profile.     

含密码子优化的SIV gag基因的DNA疫苗与rAd5疫苗构建及免疫原性评价

目的 构建含有SIVgag基因的DNA疫苗和重组腺病毒疫苗,为后期在SIV感染的猴模型中进行多载体疫苗联合免疫策略的治疗效果评价奠定基础.方法 将SIV gag基因按照哺乳动物偏嗜密码子进行优化并构建至pVR载体,作为DNA疫苗.以Western Blot方法比较优化前后gag基因表达水平.将优化后的gag基因插入重组腺病毒载体,构建rAd5-SIVgag疫苗.在BALB/c小鼠中分别比较DNA疫苗及rAd5-SIV.gag疫苗单独及联合免疫的效果.结果 密码子优化的SIVgag基因的表达水平远高于野生型SIVgag基因.重组腺病毒疫苗免疫一次或两次诱导的细胞免疫反水平分别高于DNA疫苗免疫一次或两次.两种疫苗联合免疫的反应水平与腺病毒疫苗免疫两次的水平相当,高于DNA疫苗单独免疫及腺病毒疫苗单独免疫一次的结果.结论 成功优化了SIV gag基因,使其不依赖Rev高水平表达;成功构建了表达优化后SIV gag基因的DNA疫苗和rAd5疫苗,可以在小鼠体内诱导较强的gag基因特异性CTL应答.     

Endogenous interleukin-18 is involved in immunity to Leishmania donovani but its absence does not adversely influence the therapeutic activity of sodium stibogluconate

Immunity to Leishmania donovani is associated with an interleukin (IL)-12 driven T helper 1 (Th1) response. In addition, the ability to respond to chemotherapy with sodium stibogluconate (SSG) requires a fully competent immune response and both Th1 and Th2 responses have been shown to positively influence the outcome of drug treatment. In the present study, the influence of IL-18, which can modulate both interferon (IFN)-gamma and IL-4 production, on the outcome of primary L. donovani infection and SSG therapy following infection was assessed using BALB/c IL-18-deficient and wild type mice. IL-18 deficiency was associated with an increased susceptibility to L. donovani infection, evident by day 40 post infection, resulting in higher parasite burdens in the spleen, liver, and bone marrow compared with wild type control animals. Infected IL-18-deficient mice had significantly lower splenocyte concanavalin A (ConA) induced IFN-gamma production as well as lower serum IL-12 and IFN-gamma levels, indicating a reduced Th1 response. However, drug treatment was equally effective in both mouse strains and restored serum IL-12 and IFN-gamma levels, and IFN-gamma production by ConA stimulated splenocytes of IL-18-deficient mice, to levels equivalent to similarly treated wild type mice.     

Polyclonal hypergammaglobulinemia and formation of hydrophobic immune complexes in porcine reproductive and respiratory syndrome virus-infected and uninfected pigs

Infection of young conventional, domestic pigs with porcine reproductive and respiratory syndrome virus (PRRSV) strains VR2332 and JA142 resulted in a rapid, progressive increase in serum IgG reaching maximum levels of 20-30 mg/mL at about 3 weeks post infection (p.i.), which were maintained until at least 63 days p.i., whereas the level of serum IgG remained at 4-6 mg/mL in sham infected pigs. In most of the VR2332 and JA142-infected pigs hypergammaglobulimenia was associated with the formation of hydrophobic, 150-300-kDa IgG-containing immune complexes that bound in the presence of 0.1% Tween 20 to ELISA plates that were not coated with any antigen. The ELISA plate-binding activity remained low in most infected pigs, but reached high levels in some JA142-infected pigs. Binding of the immune complexes was also observed, but at a lower level, to uncoated ELISA plates in the peptide ELISA for anti-PRRSV Abs. The immune complexes bound to uncoated ELISA plates with a much lower affinity than Abs to plates coated with peptides containing the appropriate epitopes. The immune complexes also bound to HerdChek ELISA plates, but because of low binding affinity for these plates, the bound complexes were removed by the repeated washes with Tween 20 solution. Overall the PRRSV-induced hypergammaglobulinemia and generation of ELISA plate-binding immune complexes resembled those observed in mice infected with the closely related lactate dehydrogenase-elevating virus (LDV) and thus, like the latter, seem a result of a polyclonal activation of B cells. We also found that sera of a group of older sows possessed high levels of IgG as well as of ELISA plate-binding immune complexes, in spite of being PRRSV infection negative by all criteria presently available. On the other hand, sera from wild hogs contained no ELISA plate-binding IgG in spite of possessing high total serum IgG levels.     

Sequentially immune-induced antibodies could cross-neutralize SARS-CoV-2 variants

Background : The Omicron (B.1.1.529) SARS- COV- 2 variant has raised serious con-cerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein. Since the vaccine-i nduced neutralizing antibody targets are the spike protein, this may lead to the possibility of vaccine-i nduced hu-moral immunity escape.Methods : We measured the neutralizing activity in vitro for Omicron and compared this with wild type (WH- 09) and Delta variants in human and monkey sera from dif-ferent types of immunity. The monkey sera samples were collected at 1 and 3 months post three- dose inactivated (PiCoVacc) and recombinant protein (ZF2001) vaccination. Human sera were collected from 1 month post three- dose inactivated vaccination. Results : In inactivated vaccine sera, at 1/3 months post three- dose, geometric mean titers (GMTs) of neutralization antibody (NAb) against the Omicron variant were 4.9/5.2- fold lower than those of the wild type. In recombinant protein vaccine sera, GMTs of NAb against Omicron were 15.7/8.9- fold lower than those of the wild type. In human sera, at 1 month post three- dose inactivated vaccination, GMTs of NAb against Omicron were 3.1- fold lower than those of the wild type. Conclusion : This study demonstrated that despite a reduction in neutralization titers, cross- neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.     

An essential role for Rxr alpha in the development of Th2 responses

A viable hypomorphic allele of mouse retinoid X receptor α (Rxrα) was created by random germline mutagenesis. The mutation (I273N) alters the ligand binding and heterodimerization domain, and causes a 90% decline in ligand‐inducible transactivation. Homozygotes develop progressive alopecia and dermal cysts, and progressive exaggeration of Th1 and loss of Th2 responses to antigen. Th1 skewing is directly caused by aberrant function of both antigen‐presenting cells and naïve CD4 T cells; the predominant Th1 response to antigen is attributable to decreased suppression of regulatory T cells in mutant mouse. Dietary depletion of vitamin A in Th2‐prone wild‐type mice mimics the immune phenotype caused by the mutation. Hence, RXRα plays an important post‐developmental role in the regulation of adaptive immune responses, and provides a plausible link between nutritional environment and the type of adaptive response that results from immunization. See accompanying commentary http://dx.doi.org/10.1002/eji.200535588     

Embracing nature’s complexity: Immunoparasitology in the wild

A wealth of research is dedicated to understanding how resistance against parasites is conferred and how parasite-driven pathology is regulated. This research is in part driven by the hope to better treatments for parasitic diseases of humans and livestock, and in part by immunologists who use parasitic infections as biomedical tools to evoke physiological immune responses. Much of the current mechanistic knowledge has been discovered in laboratory studies using model organisms, especially the laboratory mouse. However, wildlife are also hosts to a range of parasites. Through the study of host-parasite interactions in these non-laboratory systems we can gain a deeper understanding of parasite immunology in a more natural, complex environment. With a focus on helminth parasites, we here explore the insights gained into parasite-induced immune responses through (for immunologists) non-conventional experimental systems, and how current core findings from laboratory studies are reflected in these more natural conditions. The quality of the immune response is undoubtedly a central player in susceptibility versus resistance, as many laboratory studies have shown. Yet, in the wild, parasite infections tend to be chronic diseases. Whilst reading our review, we encourage the reader to consider the following questions which may (only) be answered by studying naturally occurring parasites in the wild: a) what type of immune responses are mounted against parasites in different hosts in the wild, and how do they vary within an individual over time, between individuals of the same species and between species? b) can we use wild or semi-wild study systems to understand the evolutionary drivers for tolerance versus resistance towards a parasite? c) what determines the ability of the host to cope with an infection and is there a link with the type of immune response mounted? d) can we modulate environmental factors to manipulate a wild animal’s immune response to parasitic infections, with translation potential for humans, wildlife, and livestock? and e) in context of this special issue, what lessons for Type 2 immunity can we glean from studying animals in their natural environments? Further, we aim to integrate some of the knowledge gained in semi-wild and wild settings with knowledge gained from traditional laboratory-based research, and to raise awareness for the opportunities (and challenges) that come with integrating a multitude of naturally-occurring variables into immunoparasitological research.     

Expression of rabbit IL-4 by recombinant myxoma viruses enhances virulence and overcomes genetic resistance to myxomatosis

Rabbit IL-4 was expressed in the virulent standard laboratory strain (SLS) and the attenuated Uriarra (Ur) strain of myxoma virus with the aim of creating a Th2 cytokine environment and inhibiting the development of an antiviral cell-mediated response to myxomatosis in infected rabbits. This allowed testing of a model for genetic resistance to myxomatosis in wild rabbits that have undergone 50 years of natural selection for resistance to myxomatosis. Expression of IL-4 significantly enhanced virulence of both virulent and attenuated virus strains in susceptible (laboratory) and resistant (wild) rabbits. SLS-IL-4 completely overcame genetic resistance in wild rabbits. The pathogenesis of SLS-IL-4 was compared in susceptible and resistant rabbits. The results support a model for resistance to myxomatosis of an enhanced innate immune response controlling virus replication and allowing an effective antiviral cell-mediated immune response to develop in resistant rabbits. Expression of IL-4 did not overcome immunity to myxomatosis induced by immunization.     

Increased levels of IgE and autoreactive, polyreactive IgG in wild rodents: implications for the hygiene hypothesis

To probe the potential role of Th1 versus Th2 reactivity underlying the hygiene hypothesis, intrinsic levels of Th1-associated and Th2-associated antibodies in the serum of wild rodents were compared with that in various strains of laboratory rodents. Studies using rat lung antigens as a target indicated that wild rats have substantially greater levels of autoreactive, polyreactive immunoglobulin G (IgG), but not autoreactive, polyreactive IgM than do laboratory rats, both on a quantitative and qualitative basis. Increased levels of serum IgG and IgE were observed in both wild rats and wild mice relative to their laboratory-raised counterparts, with the effect being most pronounced for IgE levels. Further, wild rats had greater intrinsic levels of both Th1- and Th2-associated IgG subclasses than did lab rats. The habitat (wild versus laboratory raised) had a more substantial impact on immunoglobulin concentration than did age, strain or gender in the animals studied. The presence in wild rodents of increased intrinsic, presumably protective, non-pathogenic responses similar to both autoimmune (autoreactive IgG, Th1-associated) and allergic (IgE, Th2-associated) reactions as well as increased levels of Th1-associated and Th2-associated IgG subclasses points toward a generally increased stimulation of the immune system in these animals rather than a shift in the nature of the immunoreactivity. It is concluded that, at least to the extent that feedback inhibition is a controlling element of immunoreactivity, an overly hygienic environment may affect the threshold of both types of immune responses more so than the balance between the different responses.     

Aujeszky's disease vaccination and infection of pigs with maternal immunity: Effects on cell- and antibody-mediated immunity

Summary SCC, ADV-SCC, ADV-ADCC and ADV-LYST as well as ND₅₀-titres of neutralizing serum antibodies were examined in 36 passively immune pigs, 25 of which were vaccinated at 3 weeks of age and partly revaccinated 3 weeks later. Twenty-five vaccinated animals and 8 non-immune control pigs were challenged with infectious ADV.Independent of the state of maternal immunity the cytotoxic response of the white blood cells from all the animals was low at WPP 3 but rose with increasing age. ADV-LYST occurred only in some of the animals. A single vaccination evoked no significant effect on our immune parameters, but revaccination led to higher ADV-LYST and ADV-ADCC. In pigs vaccinated at WPP3 the neutralizing serum titres decreased gradually, similar to unvaccinated animals, indicating that the antibodies were of maternal origin. However, after vaccination at WPP6, no further decline of ND₅₀-titres could be detected, pointing to a limited antibody production. Animals vaccinated at WPP3 and revaccinated 3 weeks later showed a significant increase of serum neutralizing titres.Whereas the controls showed typical symptoms of Aujeszky's disease, the immune animals, especially the unvaccinated passively immune pigs, showed only elevated temperatures and most of them excreted small amounts of ADV.The development of cellular immunity after infection was rather similar within the maternally immune group independent whether the animals had been vaccinated or not, but ADV-ADCC and ADV-LYST showed a more rapid progress within the vaccinated group than in the non-vaccinated group and the non-immune control group. Infection resulted in significantly higher ND₅₀ titres in vaccinated and revaccinated animals than in unvaccinated animals, indicating a secondary response in those pigs. Thus, ADV sensitization of lymphocytes had been evoked by vaccination despite the presence of maternal antibody.The interpretation of the results was complicated by great individual and litter-dependent variations of the immune parameters.Abbreviations ADV Aujeszky's disease virus - ADV-ADCC antibody-dependent cell-mediated cytotoxicity against ADV infected cells - ADV-LYST lymphocyte stimulation by ADV - ADV-SCC spontaneous cell-mediated cytotoxicity against ADV infected cells - CTI cytotoxic index(ices) - DPI day post infection - LYST lymphocyte stimulation - SCC spontaneous cell-mediated cytotoxicity - SI stimulation index(ices) - WPP week post partum - WPV week post vaccination - WPRV week post revaccination With 5 Figures     

Coevolution of host and virus: the pathogenesis of virulent and attenuated strains of myxoma virus in resistant and susceptible European rabbits

Myxoma virus was introduced into the European rabbit population of Australia in 1950. Although the virus was initially highly lethal in rabbits, there was rapid selection for less virulent strains of virus and innately resistant rabbits. To investigate the basis of resistance to myxoma virus, we have compared the pathogensis of the virulent strain of myxoma virus originally released into Australia and an attenuated, naturally derived field strain of myxoma virus. This was done in laboratory rabbits, which have not been selected for resistance, and in wild rabbits that have developed significant resistance. Wild rabbits were able to recover from infection with virus that was always lethal in laboratory rabbits. Laboratory rabbits were able to control and recover from infection with attenuated virus. This virus caused a trivial disease in wild rabbits. There was little difference between laboratory and wild rabbits in titers of either virulent or attenuated virus in the skin at the inoculation site. However, resistant wild rabbits had a 10- to 100-fold lower titer of virulent virus within the lymph node draining the inoculation site and controlled virus replication in tissues distal to the draining lymph node. Replication of virus in lymphocytes or fibroblasts cultured from wild and laboratory rabbits demonstrated that resistance was not due to altered cellular permissivity for replication. Neutralizing antibodies were present in both susceptible and resistant rabbits, suggesting that these have no significant role in resistance. We hypothesise that resistance is due to an enhanced innate immune response that allows the rabbit to mount an effective cellular immune response.     

调节性T细胞及其CD45亚群在肝移植免疫耐受中的相关研究

调节性T细胞(Tr)作为一种具有免疫抑制功能的细胞在器官移植免疫耐受中发挥了重要作用.它通过细胞接触抑制排斥反应发生、诱导移植免疫耐受,并且这种免疫抑制具有免疫过继作用.其中CD45亚群被认为是Tr中抑制功能较强的一群细胞,在移植免疫耐受中发挥着重要作用.而肝脏作为一种免疫特惠器官,与其他器官移植相比更易产生免疫耐受....     

乙型脑炎野毒株和弱毒株（SA14-14-2）在豚鼠体内的病毒血症比较试验

目的 利用豚鼠病毒血症的产生强度对乙型脑炎野毒株和弱毒株病毒毒力进行评价.方法 以不同乙脑野毒株和减毒株及其母株病毒分别接种豚鼠,观察不同时间产生病毒血症的水平.结果 接种后1 d和3 d,不同乙脑野毒株均可检测到不同水平的病毒血症（1.00～3.40 lg pfu）,以相同滴度（104pfu）的病毒接种豚鼠时,疫苗株母株SA14产生较高水平的毒血症（2.41～3.40 lg pfu）并至少持续3 d,而SA14-14-2疫苗株未产生毒血症.结论 豚鼠病毒血症的产生强度可以作为一种新的方法对乙型脑炎病毒的减毒和疫苗株的毒力进行评价.     

Some cases of lymphoid leukosis in captive wild birds

A total of 1,234 post mortem examinations of captive wild birds was carried out during a 5-year observation period. Six cases of lymphoid leukosis were found and their pathological features are described.     

Gender difference in cell-mediated immunity after thermal injury is mediated, in part, by elevated levels of interleukin-6

The gender difference in normal immune function has been well documented, however, there is only limited information regarding whether such a difference occurs after injury. To investigate this, we examined cell-mediated immune responses in male and female mice given a 15% total body surface area dorsal scald or sham injury. Both delayed-type hypersensitivity (DTH) and splenocyte proliferative responses were significantly suppressed in males at 1 day and in females at 7 and 10 days post burn (P < 0.01). The decreased splenocyte proliferation was found to be macrophage-dependent and suppression of both immune parameters corresponded with elevated interleukin-6 (IL-6) levels. Furthermore, post-burn treatment with an anti-IL-6 antibody partially restored the DTH response in males at 1 day and females at 10 days post injury and completely restored splenocyte proliferation. These data demonstrate a possible mechanism for the gender difference in cell-mediated immune responses after thermal injury.     

Central memory CD4 cells are an early indicator of immune reconstitution in HIV/AIDS patients with anti-retroviral treatment

The number of central memory cells among the CD4+ T cells and the of activation of CD8+ T cells is believed to be a better indicator of immune restoration in patients on antiretroviral therapy (ART) than the absolute numbers of CD4(+) and CD8+ T cells alone. In the current study, we investigated the changes in the CD4(+) T cell subsets and their association with immune reconstitution and immune activation at early stages of ART. A prospective study was performed in 21 asymptomatic treatment-naive HIV-infected patients with CD4(+) T cells less than 350 cells/μl. Blood samples were evaluated at base line, and at 2, 4, 8 and 12 weeks' post antiretroviral therapy (ART). A biphasic increase of CD4(+) T cells, central memory CD4 cells (CD4 CM) and CD4 na?ve cells were observed after ART, with a rapid increase before week 4. Change in CD4 CM at week 4 positively correlated with the change in CD4(+) T cells at weeks 12 post ART, and negatively correlated with the change in CD8(+)CD38(+) T cells at weeks 12 post ART. We conclude that CD4 CM cells are a major contributor to early immune reconstitution in treatment-naive HIV-infected patients with delayed ART, and might be an early indicator for immune reconstitution.