Kinetics of inflammatory cytokines in the clearance of non-typeable Haemophilus influenzae from the lung

Levels of the pro-inflammatory cytokines TNF-x and TNF-y were measured from the time of infection to the time of complete clearance of non-typeable Haemophilus influenzae (NTHi) from the lung in immune and non-immune rats. Mucosal immunization facilitated production of significant levels of TNF-x as early as 30 min post-pulmonary challenge with NTHi in immune animals. Following the peak at 2h, rapid decline of TNF-x levels occurred from the alveolar spaces. Levels of TNF-x in non-immunized animals increased at a slower rate, peaked at a lower concentration and were slower to decline. The significantly larger number of macrophages seen in the immune animals at 1 h after bacterial challenge could partially account for the higher levels of TNF-x. interferon-y was not detected in immune or non-immune rats at any time point before NTHi clearance after pulmonary challenge. Study of the kinetics of TNF-x release demonstrates that immunized animals control the release of pro-inflammatory cytokines more effectively than non-immunized animals for enhanced clearance of bacterial infection from the lung

Characteristics of the immunological response in the clearance of non-typeable Haemophilus influenzae from the lung

Clearance of non-typeable Haemophilus influenzae (NTHi) from the respiratory tract was investigated, over time, in immune and non-immune rats. A triphasic pattern characterized the clearance of bacteria from the lungs. Mucosal immunization enhanced bacterial clearance from the lungs in each of the three phases compared with clearance from non-immunized animals. Total clearance of bacteria was observed from lung tissue by 12h in immune animals and 24h in non-immune animals (peaking at 8h post-challenge), compared with non-immune animals (peaking at 12h post-challenge). Systematically derived and locally produced NTHi-specific IgA and IgG correlated with enhanced bacterial clearance during the secondary phase. This model demonstrates that immunized animals up-regulate and resolve inflammatory responses to pulmonary infection more rapidly than the non-immunized controls

Optimisation of oral immunization through receptor-mediated targeting of M cells

Only a small number of oral vaccines are available for routine immunizations despite a significant research effort and a number of obvious advantages over parenteral vaccination. The major roadblock in the development of oral vaccines has been mostly attributed to a lack of ability to specifically target antigen to the mucosal immune system of the gastrointestinal tract. This commentary examines the accessing of M cells through receptor interaction on the apical surface of the cell in order to enhance the efficiency and efficacy of oral immunization. Three challenges have been identified (1) the availability of appropriate experimental models to study M cell targeting and transcytosis; (2) appropriate tools for investigating the specificity of targeting; (3) the identification of priority targets on the apical surface of M cells

Challenges for the development of vaccines against Haemophilus influenzae and Neisseria meningitidis

The development of protein–polysaccharide conjugate vaccines has had a major impact on Haemophilus influenzae type b disease. The application of this technology to Neisseria meningitidis is also striking, particularly for serogroup C. However, significant challenges exist for the development of vaccines against non-typeable H. influenzae and against N. meningitidis serogroup B. Issues such asnon-vaccine-strain replacement and correlates of protection need to be addressed as well as the longer-term implications of vaccination against what are essentially ‘normal’ microflora

Kintetics of inflammatory cytokines in the clearance of non-typeable Haemophilus influenzae from the lung

Abstrac

Nontypeable Haemophilus influenzae : pathogenesis and prevention

Respiratory tract infections associated with nontypeable Haemophilus influenzae (NTHi) are a major cause of morbidity and mortality in both developed and nonindustrialized nations. The success of this organism as a colonizer and pathogen is due to its lack of reliance on any single mechanism of attachment and its ability to respond rapidly to host defense mechanisms by antigenic variation of proteins and enzymes. First we review the interaction between NTHi and the human host, with particular emphasis on mechanisms of adhesion, increased mucin production, and evasion of host defenses via immunoglobulin A (IgA) proteases, epithelial cell entry, and antigenic variation. Then we review vaccine strategies with emphasis on the potential of outer membrane components of NTHi to stimulate appropriate humoral and cellular immune mechanisms for prevention of infection or immunomodulation of chronically infected individuals

Vaccines and mucosal immunisation

The earliest attempts to protect humans against infectious diseases and toxins were by administering foreign substances to mucosal membranes, predominantly by the oral route. In the late 1880s, significant attention was given to the concept of ‘local’ immunisation, and the discipline of mucosal immunology was born in the early 1900s. However, despite the early enthusiasm, progress has been slow, with few mucosal vaccines being efficacious. The complexities of mucosal immune regulation and the lack of appropriate antigen delivery systems which can access mucosal inductive sites, have remained substantial obstacles. Recent studies demonstrating compartmentalisation of the common mucosal immune system create further challenges for the development of organ-specific vaccines. In the 21st century, our knowledge of mucosal immunoregulatory mechanisms, coupled with new technology for antigen delivery and immunomodulation will provide the necessary know–how to see the development and widespread use of mucosal vaccines for both preventative and therapeutic use

Mucosal immunization against respiratory bacterial pathogens

Bacterial respiratory diseases remain a major cause of morbidity and mortality throughout the world. The young and the elderly are particularly susceptible to the pathogens that cause these diseases. Therapeutic approaches remain dependent upon antibiotics contributing to the persistent increases in antibiotic resistance. The main causes of respiratory disease discussed in this review are Mycobacterium tuberculosis, Corynebacterium diphtheriae, Bordatella pertussis, Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa. All these organisms initiate disease af the mucosal surface of the respiratory tract and thus the efficacy of the host's response to infection needs to be optimal at this site. Vaccines available for diseases caused by many of these pathogens have limitations in accessibility or efficacy, highlighting the need for improvements in approaches and products. The most significant challenges in both therapy and prevention of disease induced by bacteria in the respiratory tract remain the development of noninjectable vaccines and delivery systems/immunization regimens that improve mucosal immunity

Mucosal immunity in the lung and upper airway

The mucosal surfaces of the lungs and upper airways are common sites for infection. Extensive studies of the mechanisms associated with immune responses in the respiratory tract have found that understanding the system is challenging and involves many complex interactions to prevent and eliminate infection. Immune protection against diseases transmitted through the respiratory tract requires an understanding of the important aspects associated with beneficial, detrimental or ineffective immune responses. Two critical aspects of an immune response against a pathogen are that of the inductive stage, either induced by vaccination or primary infection, and the effector stage, the ability to recognise, respond to and eliminate the infection without detriment to the host. An immunisation strategy must not only have a measure of the induced antigen specific response, but this response must also be protective

Programmed inflammatory processes induced by mucosal immunisation

Inflammation is essential to repair tissue damaged by physical, microbial or allergic mechanisms. Inappropriately zealous responses lead to destructive pathology or chronic disease cycles, whereas ideal outcomes are associated with complete and rapid restoration of tissue structure and function. The establishment of a rodent model investigating the different immune responses to non-typeable Haemophilus influenzae infection in both the lung and the ear indicate an ability to clear bacteria and reduce inflammation following mucosal immunisation. Lung histochemistry, upregulaion of macrophages and polymorphonuclear neutrophils, recruitment of yo+ and CD8+ T cells, cytokine levels and depletion studies all support the hypothesis that mucosal immunisation facilitates control of the immune response resulting in enhanced bacterial clearance and programming of inflammation which limits damage and promotes the rapid restoration of structural normality