Nasal mucosal administration of chitin microparticles boosts innate immunity against influenza A virus in the local pulmonary tissue.

Influenza virus infection remains a major health concern due to morbidity and mortality associated with epidemics and occasional pandemics. The absence of acquired immunity to antigenically distinct, emerging virus strains stresses the need for a generic drug that protects independent of vaccination. Here, we demonstrate that prophylactic administration of chitin microparticles (CMP) via the intranasal route significantly reduced lung viral titres and clinical signs.

Determining ligand specificity of Ly49 receptors.

Ly49 receptors in rodents, like KIR in humans, play an integral role in the regulation of NK cell activity. Some inhibitory Ly49 are known to interact with specific MHC I alleles to maintain tolerance to self tissues, and NK activation is triggered upon the loss of inhibitory signals due to pathological downregulation of self MHC I. Although a virally encoded ligand has been identified that can trigger NK cytotoxicity through an activating Ly49, some activating Ly49 also recognize MHC I and the role of most activating receptors in NK effector function remains poorly defined.

The contribution of naturally occurring IgM antibodies, IgM cross-reactivity and complement dependency in murine humoral responses to pneumococcal capsular polysaccharides.

Immunogenicity of 12 capsular polysaccharides (CPS) from Streptococcus pneumoniae did not correlate with pre-existing levels of natural IgM anti-CPS antibodies in mice. Immunization of mice with individual CPS, with the exception of type 14 (the only neutral CPS tested), increased serum IgM that also bound other CPS serotypes independent of structural similarity or commonly known contaminants. Surprisingly only IgM response to type 4 (which has a small immunodominant epitope) was dependent on either complement C3 or complement receptors CD35/CD21.

Role of lipopolysaccharide in the induction of type I interferon-dependent cross-priming and IL-10 production in mice by meningococcal outer membrane vesicles.

We investigated the contribution of lipopolysaccharide (LPS) to adjuvant properties of native outer membrane vesicles (NOMV), a vaccine candidate for meningococcal B disease. NOMV induce the maturation of and cytokine production by murine bone marrow-derived dendritic cells through both toll-like receptors (TLR) 2 and 4 which are mostly dependent on the signalling adaptor MyD88. NOMV are also able to induce B cell proliferation in splenocytes from LPS-hyporesponsive mice.

Lessons for tuberculosis vaccines from respiratory virus infection.

There is a worldwide epidemic of increasingly drug-resistant TB. Bacillus Calmette-Guérin vaccination provides partial protection against disseminated disease in infants but poor protection against later pulmonary TB. Cell-mediated protection against respiratory virus infections requires the presence of T cells in lung tissues, and the most effective prime-boost immunizations for Mycobacterium tuberculosis also induce lung-resident lymphocytes.

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination.

Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants.

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge.

Primary neonatal immune responses to infection or vaccines are weak when compared with those of adults. In addition, memory responses of neonatally primed animals may be absent, weak or T helper type 2 (Th2)-biased. Respiratory syncytial virus (RSV) is an important pathogen of human infants and infection during the neonatal period has been linked to the development of asthma in later life.

Primer: making sense of T-cell memory.

Protective memory is a key property of the immune system. Pathogen-associated molecular patterns of invading organisms deliver signals to pattern-recognition receptors that activate the innate immune system. Ligation of the T-cell receptor by peptides bound to MHC antigens and presented by dendritic cells, together with signals produced by the activated innate immune system, initiate T-cell responses.

On the hydrophobicity of peptides: Comparing empirical predictions of peptide log P values.

Peptides are of great therapeutic potential as vaccines and drugs. Knowledge of physicochemical descriptors, including the partition coefficient logP, is useful for the development of predictive Quantitative Structure-Activity Relationships (QSARs). We have investigated the accuracy of available programs for the prediction of logP values for peptides with known experimental values obtained from the literature.

Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells.

Interactions between dendritic cells (DC) and T cells are known to involve the delivery of signals in both directions. We sought to characterize the effects on human DC of contact with different subsets of activated CD4+ T cells. The results showed that interaction with CD25(high)CD4+ regulatory T cells (Tregs) caused DC to take on very different properties than contact with naive or memory phenotype T cells.

A role for CD44 in T cell development and function during direct competition between CD44+ and CD44- cells.

The role of CD44 in T cell biology remains incompletely understood. Although studies using anti-CD44 antibodies have implicated this cell adhesion molecule in a variety of important T cell processes, few T cell defects have been reported in CD44-deficient mice. We have assessed the requirement for CD44 in T cell development and mature T cell function by analyzing mice in which CD44(-/-) and WT cells were produced simultaneously.

Unusual case presentations associated with the CD45 C77G polymorphism.

CD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features.

Salmonella typhimurium infection triggers dendritic cells and macrophages to adopt distinct migration patterns in vivo.

The presence of an anti-bacterial T cell response and evidence of bacterial products in inflamed joints of reactive arthritis patients suggests an antigen transportation role in this disease for macrophages and dendritic cells. We have investigated the functional properties and in vivo migration of macrophages and DC after infection with Salmonella enterica serovar Typhimurium (S. typhimurium).

Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length.

Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation.

Preferential induction of CD4+ T cell responses through in vivo targeting of antigen to dendritic cell-associated C-type lectin-1.

Targeting of Ags and therapeutics to dendritic cells (DCs) has immense potential for immunotherapy and vaccination. Because DCs are heterogeneous, optimal targeting strategies will require knowledge about functional specialization among DC subpopulations and identification of molecules for targeting appropriate DCs. We characterized the expression of a fungal recognition receptor, DC-associated C-type lectin-1 (Dectin-1), on mouse DC subpopulations and investigated the ability of an anti-Dectin-1 Ab to deliver Ag for the stimulation of immune responses.

CD45 is required for type I IFN production by dendritic cells.

CD45 is a leukocyte tyrosine phosphatase, essential for normal immune responses. We have studied the function of splenic dendritic cells of CD45(+/+), CD45(-/-), CD45RABC and CD45RO transgenic mice. We show that there are increased numbers of plasmacytoid dendritic cells in CD45(-/-) mice.

IFN-alpha/beta-dependent cross-priming induced by specific toll-like receptor agonists.

Toll-like receptors (TLR) are pattern recognition receptors that have been identified as crucial in the initiation of innate immune responses against pathogens. They are thought to be involved in shaping appropriate adaptive immune responses, although their precise contribution has not yet been fully characterised. Our aim was to investigate in vivo the effect of different TLR stimuli on cellular immune responses.

A role for the transcription factor RelB in IFN-alpha production and in IFN-alpha-stimulated cross-priming.

Chimeric mice generated with bone marrow from RelB-deficient (-/-), RelB-heterozygous (+/-) and wild-type (+/+) mice were used to determine how total or partial absence of the transcription factor RelB in haematopoietic cells affects the immune response generated after lymphocytic choriomeningitis virus (LCMV) infection. In RelB(-/-) chimeras, early virus replication was enhanced and LCMV clearance was impaired. Although plasmacytoid dendritic cell numbers were similar, serum interferon (IFN)-alpha levels in RelB(-/-) and RelB(+/-) chimeras were markedly lower than in RelB(+/+) chimeras during early LCMV infection.

Modification of TLR-induced activation of human dendritic cells by type I IFN: synergistic interaction with TLR4 but not TLR3 agonists.

Upon detection of direct and indirect signs of infection, dendritic cells (DC) undergo functional changes that modify their ability to elicit immune responses. Type I interferon (IFN-alpha/beta), which includes a large family of closely related infection-inducible cytokines, represents one indirect signal that can act as a DC stimulus. We have investigated the ability of IFN-alpha/beta subtypes to affect DC function and to influence DC responses to Toll-like receptor (TLR) agonists (i.

Induction of CD8+ T cell responses through targeting of antigen to Dectin-2.

Targeted delivery of antigens to dendritic cells (DC) can be used to optimise immunisation. We investigated whether the efficacy with which immune responses are induced can be improved by targeting Ags to a C-type lectin receptor, Dectin-2. When anti-Dectin-2 mAbs were injected s.

Interaction of foot-and-mouth disease virus with dendritic cells.

Despite several decades of investigation, the manner in which foot-and-mouth disease virus (FMDV) interacts with the innate and adaptive immune compartments is not completely understood. The importance of elucidating this relationship is emphasized by the inability of current FMDV vaccines to provide long-term protection and the recent outbreaks of FMDV in formerly disease-free countries. Dendritic cells (DCs) are professional antigen-presenting cells that have evolved to monitor the environment and provide a link between the innate and adaptive immune systems.

CD45 negatively regulates tumour necrosis factor and interleukin-6 production in dendritic cells.

CD45 is known to regulate signalling through many different surface receptors in diverse haemopoietic cell types. Here we report for the first time that CD45-/- bone marrow dendritic cells (BMDC) are more activated than CD45+/+ cells and that tumour necrosis factor (TNF) and interleukin-6 (IL-6) production by BMDC and splenic dendritic cells (sDC), is increased following stimulation via Toll-like receptor (TLR)3 and TLR9. Nuclear factor-kappaB activation, an important downstream consequence of TLR3 and TLR9 signalling, is also increased in CD45-/- BMDC.

Benchmarking pK(a) prediction.

Background: pKa values are a measure of the protonation of ionizable groups in proteins. Ionizable groups are involved in intra-protein, protein-solvent and protein-ligand interactions as well as solubility, protein folding and catalytic activity. The pKa shift of a group from its intrinsic value is determined by the perturbation of the residue by the environment and can be calculated from three-dimensional structural data.

Receptor-binding sites: bioinformatic approaches.

It is increasingly clear that both transient and long-lasting interactions between biomacromolecules and their molecular partners are the most fundamental of all biological mechanisms and lie at the conceptual heart of protein function. In particular, the protein-binding site is the most fascinating and important mechanistic arbiter of protein function. In this review, I examine the nature of protein-binding sites found in both ligand-binding receptors and substrate-binding enzymes.