Mecanismos efetores da resposta imune na infecção por Bordetella pertussis / Immune response effector mechanisms to Bordetella pertussis infection

A coqueluche é uma doença infecciosa aguda, transmissível, com predileção pelo trato respiratório, caracterizada por paroxismos de tosse seca e considerada uma importante causa de morbidade e mortalidade infantil. A resposta imunológica humoral e celular do hospedeiro promove a contenção da infecção, pois essas respostas se caracterizam como importantes linhas de defesa durante a infecção e colonização da bactéria. Dessa forma, esta revisão bibliográfica procurou descrever os mecanismos mais eficazes de resposta imune contra Bordetella pertussis e abordar os mecanismos de evasão utilizados pelo patógeno.

Pertussis is a transmissible infectious disease with a predilection for the respiratory tract characterized by paroxysms of dry cough. It is considered an important cause of child morbidity and mortality. The humoral and cellular immune responses of the host promote the containment of the infection, and these responses are characterized as important lines of defense during infection and colonization of the bacterium. Thus, this literature review sought to describe the most effective immune response mechanisms against Bordetella pertussis and to address the avoidance mechanisms used by the pathogen.

Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins

There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.

Inducible protective processes in animal systems XIV: Cytogenetic adaptive response induced by EMS or MMS in bone marrow cells of diabetic Mouse

Background: Adaptive response has been well studied by employing physical and chemical agents in normal test systems, whereas in diseased conditions very little data are available

Aim of the study: To know the presence or absence of adaptive response in diseased condition, alkylating agents such as EMS or MMS have been employed in diabetic mouse

Material and methods: To induce diabetes, mice were injected with 180 mg/kg body weight of Stz. Diabetic mice were treated with conditioning [100 mg/kg body weight of EMS or 40 mg/kg body weight of MMS], challenging [300 mg/kg body weight of EMS or 160 mg/kg body weight of MMS] and combined doses of EMS or MMS with 8 h time lag. Parallelly controls were maintained. Mice were sacrificed at 24 or 48 or 72 h RTs. Bone marrow was extracted and slides were prepared by a routine air dry technique by Evans et al. [1964] to analyze the chromosomal aberrations

Results: The results show that both the alkylating agents induced exclusively chromatid type of aberrations in both diabetic and non diabetic mice, but it is to be underlined that MMS is a more potent inducer of aberrations than EMS. Eventhough, combined treatment of EMS or MMS induced significantly less chromosomal breaks compared to challenging treatment [p< 0.05] in diabetic mice, EMS induced 40% reduction of breaks, compared to 51.74% by MMS at 24 h RT. This is true to other tested RTs

Conclusion:[1] Methylating agents are a more effective inducer of adaptive response than ethylating agents in diabetic mouse. [2] Further, it is interesting to note that the percentage reduction of chromosomal breaks in diabetics is comparatively much less than in non diabetic mouse, inferring that there is variation in adaptive response between diseased and non diseased condition

Induction of immune response in broiler chickens immunized with recombinant FliC and challenged by Salmonella Typhimurium / Indução de resposta imune em frangos de corte imunizados com FliC recombinante e desafiados por Salmonella Typhimurium

The study examined (1) the immune response in broiler chickens after oral immunization with recombinant flagellin (rFliC) from Salmonella Typhimurium conjugated with sodium alginate microparticles, and the immune response enhancement in association with recombinant cholera toxin B subunit protein (rCTB) and pool of Lactobacillus spp. (PL). The immune responses were evaluated by dosage of IgY serum and IgA from intestinal fluid and immunostaining of CD8+ T lymphocytes in the cecum. The immunized animals were challenged with Salmonella Typhimurium (ST) 21 days after treatment. In all immunized groups, a significant increase (p<0.05) was observed in IgA levels (μg/mL), especially three weeks after immunization. The serum IgY levels (μg/mL) were little affected by the treatments and differed significantly among groups only in the second post-immunization week (p<0.05). After the challenge, the number of CD8+ T cells differed significantly between the treatments and negative control. Retrieval of Salmonella Typhimurium was not detected at 48 hours after the challenge in T2 (rFliC+rCTb), T3 (rFliC+PL) and T4 (rFliC+rCTB PL). The rFliC administered orally with or without rCTB and Lactobacillus spp. produces significant induction of humoral immune response, and the immunized chickens were more effective in eliminating Salmonella after challenge.

Este estudo investigou a resposta imunitária de frangos de corte após a imunização oral com flagelina recombinante (rFliC) de Salmonella Typhimurium conjugada com micropartículas de alginato de sódio, e como intensificador de resposta imune foi associada a proteína subunidade B da toxina colérica (rCTB) e pool de Lactobacillus spp. (PL). As respostas imunes foram avaliadas por dosagem de IgY sérica e IgA do fluído intestinal e imunomarcação de linfócitos T CD8+ presentes no ceco. Os animais imunizados foram desafiados aos 21 dias após tratamento com Salmonella Typhimurium (ST). Foi observado em todos os grupos imunizados um aumento significativo (p<0,05) nos níveis de IgA (μg/mL) principalmente três semanas após as imunizações. Os níveis de IgY sérica (μg/mL) foram pouco influenciados pelos tratamentos, apenas na segunda semana após imunização observou-se diferenças significativas (p<0,05) entre os grupos. Observou-se que o número de linfócitos T CD8+ apresentou diferença significativa entre os tratamentos e o controle negativo após o desafio. Quanto a recuperação de Salmonella Typhimurium, observou-se que 48 horas após o desafio já não havia detecção do agente nos grupos T2 (rFliC+rCTb), T3 (rFliC+PL) e T4 (rFliC+rCTB+PL). Concluí-se que rFliC administrada, via oral, associada ou não a Lactobacillus spp e rCTB, demonstrou induzir significativamente a resposta imune humoral e que as aves imunizadas foram mais eficientes na eliminação de Salmonella após desafio.

Evaluation of effective doses of hepatitis B immunoglobulin to eliminate hepatitis B surface antigen from infected neonates / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To determine the effective dose of hepatitis B immunoglobulin (HBIG) for clearing maternally-transmitted hepatitis B virus (HBV) from a newborn.</p><p><b>METHODS</b>Full-term neonates born to HBV-infected mothers were tested for hepatitis B surface antigen (HBsAg) and HBV DNA in venous blood, Individuals with positive results within two hours after birth were selected for study, and divided among two treatment groups: research group receiving HBIG continually adjusted to quantitative levels of neonatal HBsAg and HBV DNA levels; control group receiving standard HBIG 200IU dose. All neonates were also treated with 10 micrograms of recombinant vaccine. The decreases in HBsAg and HBV DNA over 12 months were comparatively analyzed between the two treatment groups.</p><p><b>RESULTS</b>The two treatment groups (HBIG adjusted vs. standard) were statistically similar in Apgar score (9.38+/-0.49 vs. 9.37+/-0.48), neonate body weight (3458.67+/-374.93 vs. 3558.61+/-322.85 g), maternal age (26.33+/-3.63 vs. 25.33+/-3.03), and initial HBsAg and HBV DNA levels (rank sum test Z = 1.381, and Z = 0.700, respectively) (all, P more than 0.05). Successful clearance of HBV infection within 12 months was achieved in significantly more neonates in the HBIG adjusted therapy group than in the standard therapy group (82.8% vs. 57.4%; x2 = 9.696, P less than 0.05).</p><p><b>CONCLUSION</b>Adjusting the neonatal HBIG dose according to HBsAg and HBV DNA levels can improve the success rate of clearing maternally-transmitted HBV.</p>

Establishment of a nonbacterial prostatitis model in rats using the autoimmune method: a dose-effect study / 中华男科学杂志

<p><b>OBJECTIVE</b>To establish an animal model of chronic nonbacterial prostatitis (CNP) using different doses of purified prostate protein with Freund's complete adjuvant (FCA), and to investigate the relationship of the doses with the success of the model construction.</p><p><b>METHODS</b>Thirty male Wistar rats were divided into a control (A) and 4 experimental groups (B, C, D and E) of equal number. The latter 4 groups were given multi-loci intracutaneous injection of 1.0 ml of a 1:1 mixture of purified prostate protein at 20, 40, 60 and 80 mg/ml with Freund's complete adjuvant (FCA), and meanwhile intraperitoneally injected with 0.5 ml of pertussis-diphtheria-tetanus vaccine at 0 and 30 days. On the 45th day, the rats were sacrificed for observation of the pathomorphological changes in the prostate glands with the naked eyes and microscope.</p><p><b>RESULTS</b>Different degrees of chronic inflammation were observed with different degrees of lymphocyte infiltration and interstitial hyperplasia in the experimental rats. More obvious changes were found in Groups C and D than in A, and even more significant in Group E (P < 0.05).</p><p><b>CONCLUSION</b>The rat model of CNP can be successfully established by multi-loci intracutaneous injection of 1.0 ml of a 1: 1 mixture of purified prostate protein at 40 - 60 mg/ml with FCA, and simultaneously intraperitoneal injection of 0.5 ml of pertussis-diphtheria-tetanus vaccine twice within 30 days.</p>

Study on safty of standardized specific mite-allergen immunotherapy to children with allergic rhinitis and/or asthma / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To evaluate the adverse reaction of standardized specific mite-allergen immunotherapy.@*METHOD@#One hundred and fifty-two patients diagnosed by the pediatric immunotherapy center of our hospital were treated with increasing doses of standardized specific mite-allergen injection. Before and 30 minutes after treatment, the peak expiratory flow (PEF) and pulmonary function for the maximum lung ventilation function were checked, and the adverse reactions were recorded.@*RESULT@#Six hundred and eighty-one injections were recorded. 84 injections (12.3%) caused immediate side effects, including 64 mild local adverse reactions (9.4%), 2 moderate local adverse reactions (0.3%), 18 systemic adverse reactions (2.6%) which were mild asthma, and no fatal anaphylactic shock and other serious adverse reactions were found. 50 injections (7.3%) cased delayed adverse reactions, all of which were mild local adverse reactions. The rate of immediate local adverse reactions and systemic adverse reactions in the maintenance treatment period was significantly higher than that in the initial treatment period (chi2 = 4.59, 19.82 respectively; P 0.05). The PEF change rate (-0.000 2 +/- 0.085 9) of the children at 681 injections and the MMEF change rate of the children at 109 injections (0.275 +/- 0.206) were not statistically different (t = -0.047, 1.39; P = 0.963, 0.166).@*CONCLUSION@#Standardized specific mite-allergen immunotherapy is safe for children with allergic rhinitis and/or asthma.

Desenvolvimento e manutenção de memória imunológica após imunização contra Neisseria meningitidis B com a vacina VA-MENGOC-BC / Development and maintenance of immunological memory after immunization against Neisseria meningitidis B with vaccine VA-MENGOC-BC

Neisseria meningitidis é uma das principais causas de meningite bacteriana e septicemia em todo o mundo, acometendo principalmente crianças menores de 4 anos. Atualmente, não existe uma vacina universal contra o meningococo B (MenB). A imunidade protetora contra o meningococo caracteriza-se pela presença e persistência de anticorpos bactericidas, porém pouco se sabe sobre os mecanismos de desenvolvimento desta memória sorológica. Avaliamos em modelo animal e em humanos, a geração e manutenção das células secretoras de anticorpos (ASC) e dos linfócitos B de memória (LBm) após vacinação contra MenB. Utilizamos como referência a vacina diftérica (dt ou DTP), considerada ter ótima eficácia em humanos. Para o estudo em modelo animal, grupos de 6 a 8 camundongos suíços, fêmeas, de 5 a 6 semanas, foram imunizados com 3 doses da vacina VA-MENGOC-BC ou DTP, via intramuscular, com intervalo de 2 semanas entre as doses. Aproximadamente 2, 4 ou 6 meses após a última dose, os animais receberam a dose reforço. A vacina anti-MenB induziu uma resposta primária de ASC maior que a resposta à dose reforço. Ao contrário, a resposta de ASC à vacina dT foi maior após o booster. A resposta de LBm anti-MenB permaneceu constante (média de 1%) ao longo de todo o estudo, mas a resposta ao toxóide diftérico (TD) foi maior após o booster (média de 1,9%) que após a imunização primária. A concentração de IgC, anticorpos bactericidas e opsonizantes contra MenB foi dose-dependente e foi reativada após a administração das doses reforços. Esses resultados sugerem que os LBm presentes no baço foram responsáveis pela forte resposta de anticorpos observada após a dose reforço. Para o TD, ambas ASC e LBm foram importantes na manutenção da memória sorológica. Para o estudo em humanos, seis voluntários foram imunizados com 3 doses da vacina VA-MENGOC-BC, via intramuscular, com intervalo de 6 a 7 semanas entre as doses. Seis meses após a imunização primária, os indivíduos receberam uma dose...

Neisseria meningitides is one of the leading causes of bacterial meningitis and septicemia worldwide, particularly in children less than four years old. Currently, there is no universal vaccine agoinst serogroup B meningococcus (MenB). Protective immunity against meningococcus is characterized by the presence and persistence of bactericidal antibody, but little is known about the mechanisms of development of the serological memory. In this study, we evaluated in animal model and in humans the generation and maintenance of antibody secreting cells (ASC) and memory B cell after vaccination against MenB. We used the diphtheria vaccine (dT or DTP) as a reference for efficacy in humans. Five to six-week old female Swiss mice in groups of 6 to 8 were immunized with three intramuscular injections of VA-MENGOC-BC or DTP vaccine 2 weeks apart. Approximately 2, 4 or 6 months after the last dose, mice received a booster injection of the vaccine. Vaccination against MenB induced a higher ASC primary response compared with the booster response. In contrast, ASC response to dT was higher after booster than after primary immuinization. Memory B-cell to MenB remained at constant levels (mean of 1%) during the whole study, but the response to diphtheria toxoid (TD) was higher after boosting (mean of 1.9%) when compared with the primary response. IgG, bactericidal and opsonic antibody concentrations to MenB was dose-dependent and was reactivated after booster doses. These data suggest that spleen memory B-cells were responsible for the strong boosting antibody response to MenB. For TD, both ASC and memory B-cell were important for maintenance of the serological memory. For the human study, six volunteers were immunized with three intramuscular injections of VA-MENGOC-BC 6 to 8 weeks apart. Six months after the last dose, subjects received a booster dose. Another group of volunteers (n=5) were immunized with a booster dose of dT vaccine. Three doses of vaccine...

Múltiplas doses de vacina BCG podem proteger contra asma? / Can multiple doses of BCG vaccine protect against asthma?

OBJETIVO: Comparar a vacinação com uma única dose de BCG intradérmica com a vacinação com múltiplas doses, uma das quais pela técnica de multipuntura, em relação ao efeito protetor contra o aparecimento posterior de asma. MÉTODOS: Estudo de coorte retrospectivo com 2.311 pessoas vacinadas com BCG. Os indivíduos foram classificados de acordo com o número de doses de vacina BCG recebidas (uma dose, duas doses e três ou mais doses). O tempo mínimo de acompanhamento para verificar se houve algum efeito protetor da vacina BCG em relação ao diagnóstico de asma foi de 10 anos. RESULTADOS: A amostra incluiu 1.317 pessoas (56,99 por cento) que receberam apenas uma dose do BCG, 644 (27,87 por cento) que receberam duas doses e 350 (15,14 por cento) com três ou mais doses. O número de pacientes diagnosticados com asma entre aqueles que receberam uma dose de BCG, duas doses e três ou mais doses foi, respectivamente, 216 (16,40 por cento), 107 (16,61 por cento) e 50 (14,28 por cento). Não houve diferenças significativas entre os grupos. CONCLUSÕES: Na amostra estudada, não foi observada uma redução na prevalência de diagnóstico de asma com a revacinação ou com o uso de múltiplas doses da vacina BCG.

OBJECTIVE: To compare BCG vaccination involving a single intradermal dose and that involving multiple doses, one given with the multiple puncture technique, in terms of the protective effect against the subsequent onset of asthma. METHODS: A retrospective cohort study involving 2,311 individuals having received the BCG vaccine. The patients were classified according to the number of doses of BCG vaccine administered (one; two; or three or more). The minimum follow-up period in order to determine whether there was any protective effect of BCG vaccination regarding the diagnosis of asthma was 10 years. RESULTS: The sample included 1,317 individuals (56.99 percent) who had received only one BCG dose, 644 (27.87 percent) who had received two doses, and 350 (15.14 percent) who had received three or more doses. The number of patients diagnosed with asthma among those who had received one dose, two doses and three or more doses was, respectively, 216 (16.40 percent), 107 (16.61 percent) and 50 (14.28 percent). There were no significant differences among the groups. CONCLUSIONS: In the study sample, the prevalence of asthma among individuals having received multiple doses of the BCG vaccine was no different than that observed among those having received a single dose.

Effect of early allergen immunization on the development of allergic rhinitis in mouse / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the effect of early allergen exposure on later development of allergic rhinitis in mouse.</p><p><b>METHODS</b>Twenty-four BALB/c neonates were randomly divided into 4 groups (low-dose group, high-dose group, negative control group and positive control group), each group had 6 mice. The mice were administered ovalbumin (OVA) by subcutaneous injection on day 1, 5, 12 after birth (10 μg OVA in 0.05 ml saline for low-dose group, 1000 μg OVA in 0.05 ml saline for high-dose group, only saline for negative and positive control group). Then the mice were sensitized and intranasally challenged with OVA (saline without OVA was used in negative control group) after 6 weeks. Symptoms, histopathological changes of nasal mucosa were observed, OVA-IgE in serum was examined, cytokines IL-4, IL-5 and IFN-gamma were detected in the supernatant of cultured splenic mononuclear cells.</p><p><b>RESULTS</b>Compared to the positive control group, symptoms and nasal mucosa histological changes of high-dose group was indistinctive. The level of OVA-IgE and cytokines IL-4, IL-5 (x(-) +/- s) in high-dose group [(265.11 +/- 26.29), (446.39 +/- 72.83) and (171.24 +/- 15.66) pg/ml, respectively] were significantly lower than those in positive control group [(665.85 +/- 43.15), (1113.45 +/- 30.47), (255.36 +/- 30.96) pg/ml, respectively, t value were 0.000, 0.000 and 0.009, respectively, all P < 0.05]. The level of IFN-γ in high-dose group [(319.74 +/- 56.30) pg/ml] was significantly higher than those in positive control group [(170.02 +/- 14.50) pg/ml, t = 0.000, P < 0.05]. There was no significant difference of the results between the low-dose group and positive control group.</p><p><b>CONCLUSIONS</b>Neonatal immunization with high-dose OVA inhibited the future allergic rhinitis symptoms, nasal histological changes, serum OVA-IgE levels and Th1/Th2 cytokine imbalance, resulting in the protective effect.</p>

Safety and immunogenicity of combined hepatitis A and hepatitis B vaccine according to 0 and 6 months schedule in healthy children / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the safety and immunogenicity of the Bilive(TM) combined hepatitis A and hepatitis B vaccine in healthy children.</p><p><b>METHODS</b>A total of 116 healthy children aged 1 - 10 years, who, without history of hepatitis A vaccine vaccination and anti-HAV negative, had completed the full immunization of hepatitis B vaccine were recruited in city of Changzhou in Jiangsu province. The Bilive(TM) combined hepatitis A and hepatitis B vaccine was administered according to a two-dose schedule (0, 6 months). The dosage was 250 U for hepatitis A antigen and 5 microg for hepatitis B surface antigen. The potential adverse effects were observed within 72 hours after vaccination. The serum samples were collected for the testing of anti-HAV and anti-HBs at month 1, 6 and 7 after initial dose.</p><p><b>RESULTS</b>The local and systemic adverse reactions after immunization were slight and temporary. The rates of local and systemic adverse reactions were 12.1% (14/116) and 6.0% (7/116). The sero-conversion rates of HAV were from 92.9% (92/99) to 100.0% (101/101) and the geometric mean titers (GMT) ranged from 47.0 mIU/ml to 2762.3 mIU/ml 1, 6, 7 months after initial dose. The sero-protection rate of HBV was 86.1% (87/101) before vaccination and came up to 100.0% (101/101) one month after initial dose, and the GMTs of HBV were from 894.3 mIU/ml to 3314.3 mIU/ml 1, 6, 7 months after initial dose.</p><p><b>CONCLUSION</b>The Bilive(TM) combined hepatitis A and hepatitis B vaccine has good safety and immunogenicity in healthy children who had preexisting immunity to hepatitis B virus.</p>

Current status of hepatitis B immunization and strengthened immune memory among first-year middle school students in Tianjin / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the immunization status of hepatitis B vaccine who were inoculated at birth, HBV infections and the vaccine booster effect in the first-year middle school students (12 - 14 years old).</p><p><b>METHODS</b>A cluster, stratified simplified random sampling method was administrated. The sample size was at least 218, which was calculated by Epi Info 3.3.2 software at 53% the minimum acceptable anti-HBs positive rate and 95% confidence level. A total of 250 and 236 students participated in the infection status and booster immunization effects investigation. The HBsAg, anti-HBs and anti-HBc IgG were detected by Enzyme-linked immunosorbent assay (ELISA). HBV DNA was detected by fluorescence quantitative PCR, and the diagnostic test kit were produced respectively by ABBOTT, Diasorin and Beijing Wantai Biological Pharmacy Enterprise Co.</p><p><b>RESULTS</b>For the immunization status before booster: the positive rate of anti-HBs was 62.80% (157/250), the GMT was 73.79 IU/L; the currently HBV infection rate (HBsAg and anti-HBc positive) was 2.80% (7/250). After injection, the anti-HBs positive rate was 94.92% (224/236). Compared with the before booster results, the significant difference was observed (χ(2) = 73.92, P = 0.00). The GMT was 521.15 IU/L, comparing with the before booster results, there was significant difference (t = 15.98, P = 0.00). The anti-HBs conversion rate (from negative to positive) was 91.86% (79/86) after immune-enhancement; of which, 11 students got the second dose of booster vaccine who are no-responders after first injection, in addition 8 students got the anti-HBs.</p><p><b>CONCLUSION</b>It is an effective method to put the first-year middle school students into the immune-enhancement program, so as to improve the immunization memory effect and avoid the loss of protective antibodies.</p>

High affinity soluble ILT2 receptor: a potent inhibitor of CD8(+) T cell activation

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.

Network connectivity is shown to change in C57BL/6 mice during a continuing immune response subsequent to tetanus toxoid hyperimmunization

We have already demonstrated (Stojanovic et al., 2009) a connection between tetanus toxoid (TTd) hyperimmunization and the induction of anti-phospholipid syndrome (APS) in BALB/c mice. Here we show that C57BL/6 mice subjected to an identical procedure do not exhibit any like pathology attributable to anti-phospholipid antibodies; we explain that this absence results from idiotypic connectivity. Six groups of C57BL/6 mice were hyperimmunized with TTd in aluminum hydroxide or glycerol, with or without pretreatments. Pretreated mice had been injected with polyclonal or nonspecific immune stimulators, such as complete Freund's adjuvant (CFA) or glycerol. The epitope specificity of induced antibodies was tested by indirect ELISA using a tetanus toxoid immunogen and these autoantigens: phospholipids, gangliosides, laminin. Idiotypic connectivity was tested by competitive ELISA and gauged from the degree to which the interaction of idiotypic/anti-idiotypic complementary antibodies was inhibited in the presence of immunized sera antibodies. Higher idiotypic connectivity was noted amongst pretreated mice. There was a positive correlation between higher connectivity and autoantibody levels that acted to favor the participation of natural autoantibodies in the inhibitory process. We conclude that idiotypic connectivity plays a protective role in immunization-induced autoimmunity.

Factores virales y celulares que afectan la transmisión vertical del HIV-1 / Viral and cellular factors affecting vertical transmission of HIV-1

Distintos factores virales y celulares pueden condicionar la susceptibilidad a la infección por el HIV-1. La inmunidad innata constituye la primera línea de defensa contra el virus jugando un papel fundamental en la etapa temprana de la transmisión del HIV-1 previo al desarrollo del sistema inmune adaptativo. Está constituida por elementos celulares como las células NK, granulocitos, macrófagos, células dendríticas, etc. y solubles como quimioquinas, defensinas y proteínas de unión a azúcares (lectinas) capaces de ejercer actividad antiviral. Se ha demostrado que variaciones genéticas de componentes de la respuesta inmune pueden modificar el riesgo de transmisión del HIV-1 y desarrollo de sida. Entre ellos se encuentran primordialmente los co-receptores del virus CCR5 y CXCR4, y las proteínas del complejo mayor de histocompatibilidad clase I y II. Además, características biológicas y evolutivas del HIV-1 pueden modificar el riesgo de la transmisión viral.

Viral and cellular factors may condition susceptibility to HIV-1 infection. Innate immunity represents the fist line of defense against the virus with mayor relevance at initial stages of HIV-1 transmission prior to the development of the adaptative immune system. Cellular components, such as, NK cells, granulocytes, macrophages, dendritic cells, etc and soluble factors like chemokines, defensins and sugar binding proteins (lectins) have antiviral activity. Genetic variations of immune response components can modify the risk of HIV-1 transmission and AIDS development. These mainly include viral co-receptors CCR5 and CXCR4 and HLA class I and II. Furthermore, biologic and evolutionary characteristics of HIV-1 can modify the risk of viral transmission.

Evaluation of experimental vaccines for bovine viral diarrhea in bovines, ovines and guinea pigs / Evaluación de vacunas experimentales para la diarrea viral bovina en bovinos, ovinos y cobayos

The bovine viral diarrhea virus (BVDV) infection control should be based on elimination of persistently infected animals and on immunization through vaccination, to prevent fetal infection. However, the efficacy of inactivated BVDV vaccines is variable due to its low immunogenicity. This study evaluated the humoral immune response against homologous and heterologous strains of 7 inactivated BVDV vaccines, in bovines and two experimental models (ovine and guinea pig) which might be used to test candidate vaccines. Vaccines formulated with BVDV Singer, Oregon, NADL, and multivalent, induced seroconversion in the three animal models studied, reaching antibody titres higher than 2. Vaccine containing 125C -genotype 2- only induced a low antibody response in ovine, while VS-115 NCP vaccine was not immunogenic. Furthermore, bovine sera at 60 dpv presented homologous as well as heterologous antibody response, indicating a high degree of cross-reactivity among the strains studied. However, when bovine sera were tested against the Argentine field strain 00-693, they showed the lowest levels of cross-reactivity, suggesting the need of continued surveillance to identify and characterize emerging field BVDV strains. Finally, optimal correlations between bovine-ovine and bovine-guinea pig models were observed, indicating that two alternative species could replace bovines when testing the immunogenicity of BVDV candidate vaccines.

El control del virus de la diarrea viral bovina (VDVB) se basa en la eliminación de animales persistentemente infectados, y la inmunización de hembras para prevenir infecciones fetales. La eficiencia de estas vacunas es variable por su baja inmunogenicidad. Se evaluó la respuesta inmune humoral contra virus homólogos y heterólogos de 7 vacunas experimentales inactivadas del VDVB en bovinos y en dos modelos experimentales (ovinos y cobayos). Las vacunas conteniendo VDVB Singer, Oregon, NADL y polivalentes indujeron seroconversión en los tres modelos y se alcanzaron títulos de anticuerpos mayores de 2. La vacuna con VDVB genotipo 2 VS-115, NCP, no resultó inmunogénica. La vacuna genotipo 2 125C sólo indujo baja respuesta humoral en ovinos, mientras que la VS-115, NCP, no resultó inmunogénica. En bovinos se determinó la respuesta a virus homólogos y heterólogos a 60 dpv, lo que indica un alto grado de inmunidad cruzada entre la mayoría de las cepas estudiadas. Cuando los sueros bovinos fueron ensayados con la cepa de campo de Argentina 00-693, los niveles de reacción cruzada fueron más bajos; esto sugiere la necesidad de una vigilancia epidemiológica sostenida a fin de identificar y caracterizar las cepas emergentes del VDVB. La óptima correlación en el modelo bovino-ovino y bovino-cobayo indica su utilidad para evaluar la inmunogenicidad de vacunas inactivadas de VDVB.

Study on immunogenicity of a recombinant adenovirus vaccine containing neuraminidase gene of H5N1 influenza virus (A/Anhui/1/2005) in mice / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To investigate immunity of a recombinant adenovirus vaccine (rAdV) containing codon-modified neuraminidase (Mod. NA) gene of H5N1 influenza virus in BALB/c mice and to screen for appropriate dose.</p><p><b>METHODS</b>BALB/c mice were immunized with the rAdV-Mod.NA vaccine intramuscularly twice (double injection at 0 and 4th week) in three groups, low dosage (10(5) TCID50 per dose), medium dosage (10(7) TCID50 per dose) and high dosage (10(9) TCID50 per dose). The effect of humoral and cell-mediated immunity were analysed at 5th week.</p><p><b>RESULTS</b>(1) The rAdV-Mod.NA vaccine could elicit both humoral and cell-mediated robust NA specific immunity in mice by neuraminidase inhibitor assay and IFN-gamma ELISpot assay; (2) 10(7) TCID50 per dose was the appropriate dose; (3) Peptide NA(109-124): CRTFFLTQGALLNDKH and peptide NA(182-199): AVAVLKYNGIITDTIKSW were the dominant epitopes for neuraminidase-immunized BALB/c mice, which was screened out from the whole length of neuraminidase of an H5N1 virus, A/Anhui/1l/2005.</p><p><b>CONCLUSION</b>The recombinant adenovirus NA could induce specific humoral and cellular immune responses in BALB/c after immunization, which suggest rAdV-Mod.NA vaccine was a potential vaccine candidate against H5N1 influenza and worthy of further investigation.</p>

Evaluation of immunization protection efficacy of plague subunit vaccine / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the protective efficacy of plague subunit vaccine, BALB/c mice, guinea pigs and rabbits were used in this study.</p><p><b>METHODS</b>Groups of mice (10 per group), guinea pigs (14 per group) and rabbits (6 per group) were immunized with F1 + rV270 vaccine, EV76 vaccine and alum adjuvant by intramuscular route, respectively. Serum antibody titres of mice, guinea pigs and rabbits were determined by ELISA and the immunized animals were challenged with 10(6) CFU of Y. pestis strain 141 at the 8th week after the primary immunization.</p><p><b>RESULTS</b>The immunized mice, guinea pigs or rabbits with subunit vaccine developed anti-F1 IgG titre of 41 587.3 +/- 2.1, 11 543.7 +/- 2.1 or 522.4 +/- 22.4 and elicited statistical anti-F1 IgG titre difference among them (F = 17.58, P < 0.01). The immunized mice, guinea pigs or rabbits with subunit vaccine had anti-rV270 IgG titre of 15 748.7 +/- 1.6, 12.6 +/- 1.4 or 1648.0 +/- 5.0 and induced statistical anti-rV270 IgG titre difference among them (F value was 16.34, P < 0.01). There was significant anti-F1 IgG titre difference among mice, guinea pigs and rabbits immunized with EV76 vaccine that developed anti-F1 IgG titre of 913.4 +/- 4.5, 937.0 +/- 2.0 or 342.0 +/- 12.0 (F = 23.67, P < 0.01), whereas the immunized mice, guinea pigs and rabbits with EV76 vaccine developed anti-rV270 IgG titre of 12.0 +/- 1.0, 447.0 +/- 10.0, 40.0 +/- 11.0 and there was no anti-rV270 IgG titre difference between them (F = 2.20, P = 0.1314). The immunized mice with subunit vaccine developed significantly higher anti-F1 IgG titres than immunized guinea pigs and rabbits (q value was 30.57 and 19.04, respectively, P < 0.01), and there were no anti-F1 IgG titre differences between the immunized guinea pigs and rabbits (q = 0.04, P = 0.8485). The immunized mice with subunit vaccine developed significantly higher anti-rV270 IgG titres than immunized guinea pigs and rabbits (q value was 27.10 and 19.49, respectively, P < 0.01), and there were no anti-rV270 IgG titre differences between the immunized guinea pigs and rabbits with the subunit vaccine (q = 0.25, P = 0.6187). The immunized mice with EV76 elicited higher anti-F1 IgG titres than immunized guinea pigs and rabbits (q value was 40.67 and 29.10, respectively, P < 0.01), whereas there was no difference of F1 IgG titer between immunized guinea pigs and rabbits (q = 0.06, P = 0.8098). The immunized mice, guinea pigs and rabbits with subunit vaccine provided 100% (10/10), 86% (12/14) and 100% (5/5) protection against 10(6) CFU Y. pestis of challenge, respectively. The immunized mice, guinea pigs and rabbits with EV76 vaccine gave 100% (6/6), 93% (13/14) and 100% (6/6) protection against 10(6) CFU Y. pestis of challenge respectively.</p><p><b>CONCLUSION</b>BALB/c mice is the best small animal model for valuation of protective efficacy of plague subunit vaccine. The guinea pigs showed a high individual variation for this purpose. The rabbits can be used as an alternative model for evaluating plague subunit vaccine.</p>

Modulation of protective immunity against herpes simplex virus via mucosal genetic co-transfer of DNA vaccine with beta2-adrenergic agonist

Cholera toxin, which has been frequently used as mucosal adjuvant, leads to an irreversible activation of adenylyl cyclase, thereby accumulating cAMP in target cells. Here, it was assumed that beta2-adrenergic agonist salbutamol may have modulatory functions of immunity induced by DNA vaccine, since beta2-adrenergic agonists induce a temporary cAMP accumulation. To test this assumption, the present study evaluated the modulatory functions of salbutamol co-administered with DNA vaccine expressing gB of herpes simplex virus (HSV) via intranasal (i.n.) route. We found that the i.n. co-administration of salbutamol enhanced gB-specific IgG and IgA responses in both systemic and mucosal tissues, but optimal dosages of co-administered salbutamol were required to induce maximal immune responses. Moreover, the mucosal co-delivery of salbutamol with HSV DNA vaccine induced Th2-biased immunity against HSV antigen, as evidenced by IgG isotypes and Th1/Th2-type cytokine production. The enhanced immune responses caused by co-administration of salbutamol provided effective and rapid responses to HSV mucosal challenge, thereby conferring prolonged survival and reduced inflammation against viral infection. Therefore, these results suggest that salbutamol may be an attractive adjuvant for mucosal genetic transfer of DNA vaccine.