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PubMed1996

Helicobacter pylori and gastroduodenal disorders: new approaches for prevention, diagnosis and treatment.

Prevention and treatment of H. pylori infection through immunization would be an important achievement considering the high cost of drug therapy, the appearance of antibiotic resistant strains, and the failure of drug therapy to prevent reinfection. Success hinges on determining the extent to which immunologic memory can be evoked in the stomach, and the ability to identify antigens and delivery systems which stimulate protective immunity rather than disease-promoting responses. Recent experiments by several groups have demonstrated that mice immunized orally or intragastrically (along with mucosal adjuvant) with whole H. pylori lysate, purified or recombinant urease, or purified VacA were significantly protected against challenge with virulent Helicobacter. Several vaccine candidates will enter clinical trials in humans in the near future.

Animals↗
PubMed1987

Induction of ethylenediamine hypersensitivity in the guinea pig and the development of ELISA and lymphocyte blastogenesis techniques for its characterization.

Ethylenediamine (EDA) is reported to be a poorly characterized iatrogenic and occupational contact sensitizer. To better characterize EDA hypersensitivity, a guinea pig model was employed in which the animals were exposed epicutaneously to simulate conditions of human exposure, and selected immune parameters were measured. Induction of hypersensitivity was by the Buehler occluded patch method (6 hr application/day, once a week for 3 consecutive weeks) to 10, 20, 30, or 40% EDA, using either an ethanol or acetone/corn oil vehicle. Fourteen days after the last induction, guinea pigs were challenged by patch application of 2% EDA (nonirritating). The incidence of responders for erythema in the 10% EDA (ethanol) treatment group was 83 and 50% at 24 and 48 hr, respectively. In the 10% EDA (acetone/corn oil) group the corresponding values were 50 and 17%. For 20, 30, and 40% EDA, in either vehicle, the incidence of erythema was 83 to 100%. Severity grades (scale = 0-3) for cutaneous reactions to increasing concentrations of EDA in ethanol ranged from 0.8 to 2.5; those for EDA in acetone/corn oil ranged from 0.6 to 2.8. Using an enzyme-linked immunosorbent assay developed to detect the predominant serum antibodies to EDA, it was shown that guinea pigs treated by patch application did not produce the main allergic antibody IgG specific for EDA. However, intradermal administration of an EDA-guinea pig serum albumin conjugate (EDA-GSA) to guinea pigs presensitized by patch application resulted in antibody production by 39 and 86% of the animals, at the initial and second dosing, respectively. An in vitro blastogenesis assay, using peripheral blood lymphocytes from EDA-sensitized guinea pigs, was developed to identify specific chemical allergens implicated in vivo sensitization. Maximum tritiated thymidine ([3H]TdR) incorporation by lymphocytes stimulated in vitro with EDA-GSA was observed on Day 7. Optimal antigen concentration for maximum lymphocyte proliferation ranged from 5 to 50 micrograms/ml, the major variation being attributable to interanimal differences. These results indicate that epicutaneous application of EDA in the guinea pig induces a Type IV delayed hypersensitivity; immunological memory to the hapten is maintained in cultured lymphocytes, suggesting the potential usefulness of the lymphocyte transformation test for in vitro diagnosis of chemically induced hypersensitivity in humans.

Animals↗
PubMed1996

Infections and the development of allergy.

The development of resistance or sensitivity to environmental antigens depends to a large extent on the nature of immunological memory which is generated during early antigen encounters in infancy and early childhood. The latter involves antigen-driven selection for specific Th-1-like versus Th-2-like memory cells within individual immune responses to inhaled allergens, a process which occurs in the regional lymph nodes (RLN) draining the conducting airways and which is regulated by a variety of cytokines produced by antigen-specific CD4+ and CD8+ T-cells. In addition, this T-cell selection process can theoretically be influenced by infectious agents, at two distinct levels. Firstly, infections in the airway mucosa may mobilise and activate local tissue macrophages, which migrate to RLN and secrete Th-2-inhibitory cytokines such as IL-12 and IFN alpha, and also add to IFN gamma levels in the milieu via stimulation of NK cells. Secondly, microbial stimulation via gastrointestinal tract (GIT) commensals and pathogens is recognised as the principal trigger for postnatal maturation of overall immune competence in mammals. Recent studies indicate that the speed with which the immune system in human infants attains adult-equivalent competence postnatally is inversely related to 'risk' for primary allergic sensitisation to environmental antigens. Factors which affect qualitative/quantitative aspects of microbial colonisation of the GIT during early postnatal life may accordingly have unexpected downstream effects on seemingly unrelated processes such as development of T cell memory to allergens.

Adult↗
PubMed1994

Regulation of apoptosis in the immune system.

Apoptosis in T and B lymphocytes is involved in all fundamental processes in the immune system. It is a mechanism to regulate the course of an immune response and to establish immunological memory as well as central and peripheral tolerance. Apoptosis in lymphocytes is regulated by gene products that induce or block this process. Elucidating the molecular basis for sensitivity and resistance towards induction of apoptosis is the key to the understanding of the development of the immune system, basic immune reactions and the pathogenesis of autoimmune diseases, AIDS and cancer.

Animals↗
PubMed2005

Activated mouse T-cells synthesize MHC class II, process, and present morbillivirus nucleocapsid protein to primed T-cells.

A pivotal step in the initiation of T-cell immunity is the presentation of antigenic peptides by major histocompatibility complex (MHC) expressed on antigen presenting cells. The expression of MHC class II molecules by mouse T-cells has not been shown unequivocally. In the present work, we demonstrate that activated mouse T-cells synthesize MHC class II molecules de novo and express them on their surface. Further, we have demonstrated that in vitro activated T-cells take up extra-cellular soluble nucleocapsid protein of a morbillivirus. The internalized antigen goes to antigen processing compartment as shown by co-localization of antigen and LAMP-1 using confocal microscopy. We show that activated T-cells express H2M, a chaperone molecule known to have a role in antigen presentation. Further, we demonstrate that activated T-cells process and present internalized extra-cellular antigen to primed T-cells as shown by IL-2 secretion and in vitro proliferation. The presentation of antigen by T-cells may have implications in immuno-regulation, control of infection by lymphotropic viruses and maintenance of immunological memory.

Animals↗
PubMed2005

Characterization of NKR+ T-cell subsets in human bone marrow: implications for immunosurveillance of neoplasia.

In addition to hematopoietic progenitors, human bone marrow contains mature T/NK lymphocytes. Valpha24Vbeta11 NKT-cells, a subset of NK receptor+ (NKR+) T-cells in humans, are rare in bone marrow, suggesting the presence of other NKR+ T-cells which may contribute to tumor surveillance. NKR+/- T-cells were examined in blood (PB), and bone marrow from donors (DM) and patients with active hematopoietic malignancy (PM), or in remission (PR). T-cells in PR & PM were enriched for CD56+ and CD57+ subsets, compared to DM. All marrow NKR+/- T-cell subsets were more activated than PB. PM and, surprisingly, PR marrow contained more activated cells than DM. CD8+ cells were significantly increased in all patient marrows and there was evidence of the formation of an effector/memory pool in malignant marrow. These data suggest that NKR+ T-cell enrichment in human bone marrow that has been exposed to neoplastic transformation is compatible with a role in localized tumor surveillance/eradication.

Biomarkers↗
PubMed2005

Induction of immune response to Streptococcus pneumoniae by administration of oral viridans streptococci via phosphorylcholine determinant.

Expression of the phosphorylcholine (PC) epitope was examined in 48 viridans streptococcal strains, including Streptococcus pneumoniae R36a as the positive control, and their immunogenicity to induce an S. pneumoniae-cross-reactive response was evaluated in mice. Thirteen strains were found to express the PC epitope, while no obvious association was found between the taxonomic categories and PC expression. Serum antibody responses to S. pneumoniae cells were induced in mice by intraperitoneal injection of the PC-positive, but not PC-negative, strains. The cross-reactive antibodies induced by non-pneumococcal oral streptococci were readily inhibited by free hapten PC. IgM was the sole isotype of the anti-pneumococcal and anti-PC antibodies, and the phenomenon of immunological memory was not observed. Since the anti-PC antibody is critically important for resistance against pneumococcal infection in mice, the present results indicate the possibility that PC-expressing oral commensal bacteria have a significant influence on the hosts' responsiveness to S. pneumoniae.

Animals↗
PubMed2005

P2X7 receptor-dependent ATP-induced shedding of CD27 in mouse lymphocytes.

The ATP-gated P2X7 cell surface receptor belongs to the P2X purinoreceptor family, and is expressed abundantly by immune cells. This receptor is involved in several inflammatory and immunological processes, including the secretion of IL-1 by activated macrophages. Here, we demonstrate that CD27, a cell surface molecule, which is involved in the interaction between immune cells and implicated in the immunological memory of the T and B cells, is released rapidly upon treatment with low ATP concentrations, via the activation of the P2X7 receptor. The surface expression of CD27 on the T and B cells has been shown to be down-regulated as the result of ATP treatment, and the soluble form of CD27 was detected readily in the supernatants of splenocytes, which were cultured along with ATP treatment. The shedding of CD27 was blocked by KN-62, a chemical P2X7 inhibitor, and was also efficiently triggered by treatment with 2,3-O-(4-benzoyl-benzoyl)-ATP. The shedding of CD27 from mouse splenic T cells was observed to occur within 5 min of treatment with 300 microM ATP, whereas treatment with PMA or ionomycin was not determined to trigger the shedding of CD27 until treatment had been applied for a period of at least 2 h. The ATP-induced shedding of CD27 was inhibited by treatment with the matrix metalloprotease inhibitor, GM6001, but not by treatments with BAPTA-AM, wortmannin, SB202190, or PD 98059. Therefore, we concluded that P2X7 receptor stimulation by extracellular ATP results in rapid CD27 shedding via protease activation.

Adenosine Triphosphate↗
PubMed2005

Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies.

The term asthma refers to a spectrum of wheezing syndromes resulting from airways inflammation triggered by a range of environmental stimuli, the most important of which are aeroallergens and viruses. We describe below a model for the cause of atopic asthma in which discrete sets of developmental factors governing the postnatal maturation of the immune and respiratory systems play central and complementary roles in disease causality. Within the immune system, the relevant developmental processes involve maturation of TH1 and associated innate immune functions that combat infection and concomitantly antagonize the early programming of TH2-polarized immunologic memory against inhalant allergens. Within the respiratory system, the relevant developmental processes involve intensive lung growth and airway remodeling during infancy. We hypothesize that delayed maturation of TH1-associated functions during early postnatal life increases the risk for sensitization to aeroallergens and for severe respiratory infection, resulting in airway inflammation at a crucial stage in lung development and precipitating changes in lung growth that are the harbingers of susceptibility to persistent asthma. We further hypothesize that protection of the growing lung against the effects of inflammation during infancy and early childhood has unique potential as a generic strategy for asthma prophylaxis.

Asthma↗
PubMed2004

Inverse trend between estimated worldwide frequency of major cancers and inferred infectious burdens of populations: possible role of adaptive immune system.

Regions of the world subjected to heavy infectious burdens seem to show lower incidence of cancer. The index of infectious burden in this study has been chosen to be poverty, i.e., low GDP, high infantile mortality, poor hygienic conditions, inaccessibility to modern medical infra-structures, etc. When estimates of observed cancer incidence is plotted against the GDP of 24 regions of the world, a trend line is obtained: low GDP (a proxy for high infectious burden) tends to be associated with low incidence of cancer whereas high GDP values herald higher cancer occurrences. Similarly, countries with high infantile mortality rates tend to have a lower incidence of cancer and vice versa. The data are explained in terms of the so-called "hygiene hypothesis": frequent infectious onslaughts, especially in childhood, challenge the immune system and build a strong adaptive immune system and immunological memory which prepare the body to tackle further battles down the line, such as cancer. Within this framework, the role of other factors such as diet, selenium, hardness of water, etc. in the aetiology of cancer is also briefly examined. For rigorous verification of this observation, age-adjusted cancer incidence rates for various countries must be used even though such data are not available for all the countries examined here [Bulletin of World Health Organization 62(2) (1984) 163]; where data are available [Age-adjusted death rates for cancer for selected sites (A classification) in 51 countries in 1974, Segi Institute of Cancer Epidemiology, Nagoya, Japan (Feb. 1979); Global Geocancerology, Churchill Livingstone, New York, 1986], the same trend is also observed for the age-adjusted cancer death rates, which may be used as an index of age-adjusted cancer incidence, subject to qualifications discussed in the text.

Developing Countries↗
PubMed2005

Peptides mimicking Vibrio cholerae O139 capsular polysaccharide elicit protective antibody response.

Vibrio cholerae is the etiological agent of cholera. V. cholerae serogroup O1 had been, until 1992, the only serogroup responsible for large epidemics and pandemics of cholera. In 1992, a new serotype of V. cholerae emerged in South-East Asia that caused a massive outbreak of cholera in India and neighboring countries. The new serotype was named V. cholerae O139. The main differences between V. cholerae O139 and O1 are that the former possesses a capsular polysaccharide and different lipopolysaccharide. Capsular polysaccharides are, in general, T-independent antigens giving rise to poor immune responses lacking immunological memory. In order to overcome this, monoclonal antibodies against the capsular polysaccharide of V. cholerae O139 were used to screen different phage-displayed random peptide libraries. Eight different phage clones were selected and characterized using enzyme immunoassay with the monoclonal antibodies, and then tested for specificity by competition with V. cholerae O139 capsular polysaccharide. Selected peptides were sequenced, synthesized and conjugated to bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH). The conjugated peptides were used to immunize mice. It is evident that the anti-peptide mouse antibodies bind to the V. cholerae O139 capsular polysaccharide. In addition, the anti-peptide antibodies are protective in a suckling mouse model. The protective efficacy is both specific and dose-dependent. A PCT (PCT/IT2003/000489) with the publication number WO 2004/056851 has been filed for the sequences of the eight peptides.

Animals↗
PubMed2006

Identification of novel HLA-DR1-restricted epitopes from the hepatitis B virus envelope protein in mice expressing HLA-DR1 and vaccinated human subjects.

Helper T lymphocytes that control CD8(+) T-cell and antibody responses are key elements for the resolution of infection by the hepatitis B virus and for the development of effective immunological memory after hepatitis B vaccination. We have used H-2 class II-deficient mice that express the human MHC class II molecule, HLA-DR1, to identify novel hepatitis B virus envelope-derived T helper epitopes. We confirmed the immunogenicity of a previously described HLA-DR1-restricted epitope, and identified three novel epitopes. CD4(+) T-cell immune responses against these epitopes were detected in peripheral blood mononuclear cells from HLA-DR1(+) individuals vaccinated against hepatitis B. We showed that subjects receiving the currently available hepatitis B vaccines do not develop cross-reactive T helper responses against one of the novel epitopes which are structurally variable between different hepatitis B virus subtypes. These findings highlight the need for developing vaccines against a wider range of viral subtypes, and establish humanized mice as a convenient tool for identifying new immunogenic epitopes from pathogens.

Adolescent↗
PubMed2006

[Pneumococcal vaccination: expected benefits in adults].

PURPOSE: Streptococcus pneumoniae is one of the leading causes of bacterial pneumonia, meningitis and acute otitis media in children and adults worldwide. Polysaccharide pneumococcal vaccines have been available for approximately 50 years and conjugate vaccines, which generate immunological memory even at an early age but have limited serotype coverage, have recently been developed. CURRENT KNOWLEDGE AND KEY POINTS: Although the polysaccharide vaccine is considered effective in preventing invasive pneumococcal disease (IPD) in adults, its efficacy against pneumonia and among older or immunocompromised individuals is still controversial. On the other hand, the conjugate vaccine for children allows a large reduction in the incidence of IPD and in the rate of pneumococcal colonization in the general population through herd immunity, but its serotype coverage remains low in adults and serotype replacement may be expected in the long-term. FUTURE PROSPECTS: In the present context of widespread antibiotic resistance, it is of the utmost importance to assess the expected benefits of pneumococcal vaccination, in order to be able to use it optimally in all population parts.

Adult↗
PubMed2004

A liquid hexavalent combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type B and hepatitis B: review of immunogenicity and safety.

To reduce the number of injections needed to comply with paediatric vaccination requirements, a liquid, hexavalent vaccine (DTaP-IPV-PRP-T-HBs; Hexavac; Aventis Pasteur MSD) has been developed for primary and booster vaccination of infants and toddlers. In extensive clinical studies, Hexavac has been shown to be highly immunogenic. Seroconversion or seroprotective titres of antibodies against all antigens were achieved in the majority of infants following a primary series of three doses administered at 1-2-month intervals from 2 months of age. Hexavac also induced immunologic memory, as evidenced by the anamnestic response to booster vaccination at 12-18 months of age. These responses were comparable with those seen following concomitant administration of Pentavac (DTaP-IPV//PRP-T) and monovalent hepatitis B vaccine (H-B-Vax II), and were also within the ranges observed for other relevant licensed vaccines. Clinical studies comparing the immunogenicity of Hexavac administered at either 2, 3 and 4 months or 2, 4 and 6 months demonstrated that it can be used by either vaccination schedule. A further study also supported the use of primary doses of Hexavac at 3 and 5 months with a booster at 12 months of age. Hexavac demonstrated a good reactogenicity and tolerability profile. The most frequently reported adverse events after both primary and booster doses were local reactions of redness and swelling/induration and a systemic response of mild fever, irrespective of the vaccine used for priming. Hexavac provided immunity against six important childhood diseases with a single injection at each visit.

Diphtheria-Tetanus-Pertussis Vaccine↗
PubMed2005

Could a single dose of pneumococcal conjugate vaccine in children be effective? Modeling the optimal age of vaccination.

Using incidence rates from CDC's Active Bacterial Core surveillance and immunogenicity data from the Navajo/Apache trial of pneumococcal conjugate vaccine (PCV), we used Markov modeling to predict the optimal age to give a single dose of PCV. Antibody concentration thresholds of 0.35 and 1.0 mcg/ml were considered protective. Our outcome was vaccine serotype-specific invasive pneumococcal disease (IPD) incidence at 24 months. The models predicted the optimal age to vaccinate is 5-7 months with vaccine-induced immunologic memory and 8-10 months without memory. IPD reduction ranged from 15 to 62%, depending on model parameters. A single PCV dose in infants could prevent substantial IPD.

Adolescent↗
PubMed2006

Geographic and ethnic variations of long-term efficacy and immunogenicity of hepatitis B vaccination in Hualien, a HBV hyperendemic area.

It is uncertain whether immunologic memory persists for 15 years or more after immunization and whether the efficacy of universal hepatitis B vaccination program (UHBVP) in socio-economically disadvantaged area with hyperendemicity of hepatitis B virus (HBV) infection is similar. We assayed hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) on 2839 students aged 15 years or more born before (N = 248) and after (N = 2591) UHBVP. We found that students born after UHBVP had significantly lower positive rate of anti-HBs than those born before UHBVP (44.6% versus 75.0%, p<0.0001). Seropositive rate of HBsAg for students born after UHBVP was also declined significantly (1.9% versus 9.3%, p<0.0001). Preventive fraction of UHBVP on HBsAg-seropositivity was 78% (95% confidence interval, 0.64-0.87), which was at least 10% lower than previous studies. Preventive fraction in Han Chinese (74%) and Atayal (78%) students were lower than Amis students (94%). In 2264 Han Chinese students, preventive fraction was 16% lower in those resided in rural than urban areas. These observations indicated that UHBVP was less effective in socio-economically disadvantaged area where HBV infection was hyperendemic and the long-term efficacy and immunogenicity of vaccination were modified by host factors and factors associated with urbanization.

Adult↗
PubMed2006

A review of vaccine research and development: meningococcal disease.

This paper reviews the current status of research and development of vaccines against meningococcal disease due to Neisseria meningitidis, a major cause of severe meningitis and septicemia with epidemic potential. While five serogroups (A, B, C, Y, and W135) are responsible for most of the disease, Group A remains unique in its ability to cause large scale epidemics mainly in Africa but also in Asia. The majority of cases in Europe and America are due to Groups B and C. The successful experience with Hib and pneumococcal conjugate vaccines has paved the way for the development of polysaccharide conjugate vaccines for the prevention of meningococcal disease. Widespread vaccination with Group C conjugate vaccines now in use in several European countries indicates that these vaccines are immunogenic, induce immunological memory, reduce colonization and provide herd immunity to the general population. A monovalent group A conjugate vaccine being developed at an affordable price, offers hope for the elimination of large epidemics in African countries. Multivalent (A, C, Y, W) conjugate vaccines are being developed, and one has already been licensed. However, effective global prevention of meningococcal disease will not be achievable without the development of a vaccine against Group B meningitis, for which outer membrane protein vaccines are under development.

Animals↗
PubMed2006

The humoral and cellular responses induced locally and systemically after parenteral influenza vaccination in man.

Studies of the immune response after influenza vaccination in man, with focus on the immune activity occurring locally at mucosal surfaces and in associated lymphoid tissue, provide a valuable insight into immunity to influenza. The aim of influenza vaccination is to develop immunological memory resulting in enhanced rapid specific response upon subsequent influenza encounter. The tonsils are thought to play an important role as an activating, effector and memory site for immune responses against influenza. We have shown that normally high numbers of influenza-specific antibody secreting cells (ASC) are present in the nasal mucosa of healthy adults but upon parenteral vaccination the numbers remain stable. However, a rapid transient increase in influenza-specific ASC is observed in the tonsils and peripheral blood after vaccination. In the tonsils and blood, parenteral vaccination results in a significant decrease in CD4(+) cells upon vaccination, which are probably recruited to the draining lymph node.

Antibody Formation↗