Biomedical subjects

Adrian W Zuercher

Publications and source records attributed to Adrian W Zuercher.

11 recordsLinked to original sources

PubMed2006

Intranasal immunisation with conjugate vaccine protects mice from systemic and respiratory tract infection with Pseudomonas aeruginosa.

We tested intranasal application of anti-Pseudomonas conjugate vaccine in mice. Comparison of immunisation via the intra-muscular versus intranasal routes showed the induction of equivalent levels of specific serum IgG and IgG subclasses antibodies if cholera toxin was used as an adjuvant. In contrast, secretion of specific mucosal IgA antibodies in the upper respiratory tract was only observed after intranasal immunisation together with adjuvant. Systemic and mucosal immunity was also established via the intranasal route when CpG-containing oligonucleotides were used as adjuvant. The functionality of intranasally induced antibodies was proven in vitro by opsonophagocytosis and in vivo using the burn-wound sepsis and intra-tracheal lung infection models. These results demonstrate the feasibility of intranasal immunisation against P. aeruginosa with conjugate vaccine.

Administration, Intranasal↗

PubMed2006

Food products and allergy development, prevention and treatment.

In westernized countries allergic diseases have reached epidemic proportions. Food is frequently a perpetrator of allergy but, in turn, modified food and selected food ingredients can become valuable intervention tools in the fight against allergy. There are two basic approaches towards mitigation of food allergy through nutrition: to reduce the allergenicity of raw food materials by physical, chemical or genetic methods or to influence host immunity towards a non-allergic state using various food ingredients. Dietary intervention for the prevention and therapy of allergy is an emerging field where initial findings from animal studies are now being validated in human trials. Nevertheless, to consolidate the utility of such interventions, more pre-clinical and clinical studies remain necessary.

Animals↗

PubMed2006

Antibody responses induced by long-term vaccination with an octovalent conjugate Pseudomonas aeruginosa vaccine in children with cystic fibrosis.

We assessed the serological responses over 10 years to repeated immunization of cystic fibrosis (CF) patients with an O-polysaccharide (OPS)-toxin A conjugate vaccine against Pseudomonas aeruginosa. A retrospective analysis was performed with sera from 25 vaccinated and 25 unvaccinated children treated at the same CF centre and matched for clinical management, age and gender. Yearly immunization led to sustained elevations of serum immunoglobulin G (IgG) antibody levels to all vaccine components. Eighteen unvaccinated patients but only eight vaccinated ones developed chronic pseudomonal lung infections. Infection rapidly caused further marked elevations of polysaccharide- but not toxin A-specific serum IgG in both immunized and nonimmunized patients, indicating that protection did not depend on the quantity of IgG present. However, qualitative analyses revealed that the protective capacity of specific serum IgG antibodies was linked to high affinity and to specificity for OPS serotypes rather than for lipopolysaccharide core epitopes.

Adolescent↗

PubMed2004

Prophylaxis and therapy of Pseudomonas aeruginosa infection in cystic fibrosis and immunocompromised patients.

Pseudomonas aeruginosa is an opportunistic bacterium responsible for chronic lung infection in cystic fibrosis patients, as well as nosocomial infections in immunocompromised patients. An O-polysaccharide-toxin A conjugate vaccine was evaluated for prophylaxis of P. aeruginosa in cystic fibrosis patients. Vaccination proved to be useful in preventing and/or delaying infection. Fully human monoclonal antibodies (mAb) against P. aeruginosa O-polysaccharides were developed for the treatment of immunocompromised patients in whom active immunoprophylaxis is not applicable. Characterisation of the mAb revealed high antigen specificity and avidity, as well as excellent efficacy in relevant in vitro and in vivo systems, permitting future clinical evaluation.

Animals↗

PubMed2004

Regional differences in the early mucosal immune response induced by primary inoculation of mice with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. Little is known about the characteristics of critical immunologic inductive sites within respiratory-associated lymphoid tissues (RALT) upon RSV infection. We examined the kinetics and characteristics of early mucosal RSV-specific immune responses after primary inoculation of mice. We found that the initial production of virus-specific antibodies was restricted to the organized lymphoid tissues of RALT, such as nasal-associated lymphoid tissue (NALT), cervical and bronchial lymph nodes (CLN and BLN). In addition, virus-specific IgM was produced by B cells resident in CLN and BLN, but not NALT, of mice. Finally, we observed regional differences in the pattern of RSV-specific antibodies produced by RALT; B cells within NALT and CLN produced equivalent quantities of virus-specific IgG2a and IgG2b. However, an IgG2a response predominated in BLN. Together these data demonstrate regional differences in the early mucosal immune response to RSV. Further understanding of these differences may assist the development of RSV vaccines.

Animals↗

PubMed2003

B1 cells contribute to serum IgM, but not to intestinal IgA, production in gnotobiotic Ig allotype chimeric mice.

B1 cells are a significant source of natural serum IgM, thereby serving as a first line of defense against systemic bacterial and viral infections. They can migrate to the intestinal lamina propria and differentiate into IgA-producing plasma cells and thus might play a similar role in mucosal immunity. To investigate the contribution of B1 cells to the intestinal IgA response induced by the commensal flora in immunocompetent animals, we generated gnotobiotic and conventionally reared Ig allotype chimeric mice. In this system B1- and B2-derived Abs can be distinguished based on different allotypes. FACS analysis of peritoneal cavity cells and analysis of B1- and B2-derived serum IgM indicated stable B1/B2 chimerism and the establishment of a functional B1 population. Monoassociation with either Morganella morganii, Bacteroides distasonis, or segmented filamentous bacteria induced germinal center reactions in Peyer's patches and led to the production of intestinal IgA, partially reactive with bacterial Ag. A considerable amount of serum IgM was B1 cell derived in both monoassociated and conventionally reared mice. However, most of the total as well as bacteria-specific intestinal IgA was produced by B2 cells. These data suggest that intestinal IgA production induced by commensal bacteria is mainly performed by B2, not B1, cells.

Animals↗

PubMed2003

Upper respiratory tract immunity.

Most viral infections occur via mucosal surfaces like the respiratory, gastrointestinal, or genital epithelium. The mucosal immune system is an important component of the body's defense against such infections and consequently induction of mucosal, in addition to systemic immunity, might improve vaccine efficacy. Several orally administered vaccines, for example, against poliovirus and gastrointestinal bacterial infections, have been developed and are widely used. In contrast, to date most vaccines against respiratory pathogens are applied parenterally and thus do not induce significant mucosal immunity. For the development of effective mucosal vaccines a more profound understanding of the immune mechanisms operative at mucosal surfaces and of the interplay between different mucosal compartments is needed. Moreover, factors like the dose, form of application, and type of mucosal adjuvants are critical to the induction of effective mucosal immunity. This brief review will focus mainly on the nasal route and will summarize some recent findings concerning the function of the mucosal immune system of the upper respiratory tract. Furthermore, routes of cross-immunization between distinct mucosal compartments and how they might be relevant to vaccine development will be addressed. Finally, I will outline critical factors for the rational design of nasal vaccines and in this context highlight some recent preclinical and clinical developments in the field.

Administration, Intranasal↗

PubMed2002

Distinct mechanisms for cross-protection of the upper versus lower respiratory tract through intestinal priming.

A main feature of the common mucosal immune system is that lymphocytes primed in one mucosal inductive site may home to distant mucosal effector sites. However, the mechanisms responsible for such cross-protection remain elusive. To address these we have used a model of local mucosal infection of mice with reovirus. In immunocompetent mice local duodenal priming protected against subsequent respiratory challenge. In the upper respiratory tract this protection appeared to be mainly mediated by specific IgA- and IgG2a-producing B cells, whereas ex vivo active effector memory CTL were found in the lower respiratory tract. In accordance with these findings, clearance of reovirus from the lower respiratory tract, but not from the upper respiratory tract, of infected SCID mice upon transfer of gut-primed lymphocytes depended on the presence of T cells. Taken together this study reveals that intestinal priming leads to protection of both the upper and lower respiratory tracts, however through distinct mechanisms. We suggest that cross-protection in the common mucosal immune system is mediated by trafficking of B cells and effector memory CTL.

Administration, Intranasal↗

PubMed2002

Recombinant Lactobacillus johnsonii as a mucosal vaccine delivery vehicle.

Lactobacilli are considered to be safe organisms making them attractive as vehicles for oral vaccination. We report that Lactobacillus johnsonii (Lj) partially survived simulated gastric conditions in vitro, suggesting that it could be used as an oral vaccine delivery vehicle. In order to test this approach, we used the cell wall anchored proteinase PrtB, isolated from Lactobacillus delbrueckii subsp. bulgaricus as a model antigen. Using a new vector system, we demonstrated expression of both proteinase PrtB alone and a mimotope peptide derived from tetanus toxin integrated in the sequence of proteinase PrtB (TTmim-PrtB fusion protein) on the surface of Lj. Oral immunisation of mice with recombinant Lj, expressing the TTmim-PrtB fusion protein induced a systemic IgG response against Lj and recombinantly expressed proteinase PrtB but no antibody response against the tetanus toxin mimotope suggesting that the mimotope was not sufficiently immunogenic to induce an immune response. Interestingly, a proteinase PrtB specific fecal IgA response was also induced, indicating that the proteinase PrtB fusion protein expressed as a cell surface protein on Lj can induce both systemic and local mucosal immune responses.

Administration, Oral↗

PubMed2002

Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses.

Peyer's patches are known as mucosal inductive sites for humoral and cellular immune responses in the gastrointestinal tract. In contrast, functionally equivalent structures in the respiratory tract remain elusive. It has been suggested that nasal-associated lymphoid tissue (NALT) might serve as a mucosal inductive site in the upper respiratory tract. However, typical signs of mucosal inductive sites like development of germinal center reactions after Ag stimulation and isotype switching of naive B cells to IgA production have not been directly demonstrated. Moreover, it is not known whether CTL can be generated in NALT. To address these issues, NALT was structurally and functionally analyzed using a model of intranasal infection of C3H mice with reovirus. FACS and histological analyses revealed development of germinal centers in NALT in parallel with generation and expansion of IgA(+) and IgG2a(+) B cells after intranasal reovirus infection. Reovirus-specific IgA was produced in both the upper respiratory and the gastrointestinal tract, whereas production of reovirus-specific IgG2a was restricted to NALT, submandibular, and mesenteric lymph nodes. Moreover, virus-specific CTL were detected in NALT. Limiting dilution analysis showed a 5- to 6-fold higher precursor CTL frequency in NALT compared with a cervical lymph node. Together these data provide direct evidence that NALT is a mucosal inductive site for humoral and cellular immune responses in the upper respiratory tract.

Animals↗

PubMed2002

Structural and functional differences between putative mucosal inductive sites of the rat.

Nasal-associated lymphoid tissue (NALT), bronchus-associated lymphoid tissue (BALT) and Peyer's patches (PP) were compared structurally and functionally using a model of local mucosal infection of rats with reovirus. Histological analyses showed that BALT lacks the typical lymphoid organization found in NALT and PP. After local reovirus infection, germinal centers developed in NALT with appearance of IgA+ cells, whereas no germinal centers or isotype-switched cells were found in BALT. Production of reovirus-specific IgA was observed in NALT and PP, but only small amounts of specific IgA were secreted by BALT. Both NALT and BALT showed considerable production of IgG2b, whereas this isotype was poorly produced by PP. These data reveal profound qualitative differences between these three mucosal sites, and strongly suggest that BALT is not a mucosal inductive site for reovirus-specific immune responses in the rat.

Animals↗