Prion diseases: immunotargets and therapy.

Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases.

Restricted aeroallergen access to airway mucosal dendritic cells in vivo limits allergen-specific CD4+ T cell proliferation during the induction of inhalation tolerance.

Chronic innocuous aeroallergen exposure attenuates CD4(+) T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11b(lo) and CD11b(hi) AMDC and the delivery of OVA to airway draining lymph nodes by CD8α(-) migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4(+) T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4(+) T cells.

1,25-dihydroxyvitamin D3 enhances the ability of transferred CD4+ CD25+ cells to modulate T helper type 2-driven asthmatic responses.

The severity of allergic diseases may be modified by vitamin D. However, the immune pathways modulated by the active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], are yet to be fully elucidated. In this study, naturally occurring CD4(+) CD25(+) cells from the skin-draining lymph nodes (SDLN) of mice treated with topical 1,25(OH)(2)D(3) had an increased ability to suppress T helper type 2 (Th2) -skewed immune responses. CD4(+) CD25(+) cells transferred from mice treated with topical 1,25(OH)(2)D(3) into ovalbumin (OVA) -sensitized mice challenged intranasally with OVA 18 hr later, significantly suppressed the capacity of airway-draining lymph node (ADLN) cells to proliferate and secrete cytokines in response to further OVA stimulation ex vivo. The CD4(+) CD25(+) cells from 1,25(OH)(2)D(3)-treated mice also reduced airway hyperresponsiveness and the proportions of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF). To test the effect of 1,25(OH)(2)D(3) on cells able to respond to a specific antigen, CD4(+) CD25(+) cells were purified from the SDLN of OVA-T-cell receptor (TCR) transgenic mice treated 4 days earlier with topical 1,25(OH)(2)D(3). CD4(+) CD25(+) cells from OVA-TCR mice treated with 1,25(OH)(2)D(3) were able to alter BALF cell content and suppress ADLN responses to a similar degree to those cells from non-transgenic mice, suggesting that the effect of 1,25(OH)(2)D(3) was not related to TCR signalling. In summary, topical 1,25(OH)(2)D(3) increased the regulatory capacity of CD4(+) CD25(+) cells from the SDLN to suppress Th2-mediated allergic airway disease. This work highlights how local 1,25(OH)(2)D(3) production by lung epithelial cells may modulate the suppressive activity of local regulatory T cells.

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma.

Airways hyperresponsiveness (AHR) is one of the major clinical features of allergic airways disease including allergic asthma, however the immunological mechanisms leading to the induction and regulation of this disorder are not fully understood. In this review we will summarise the evidence of a number of studies, principally in murine models of AHR, suggesting a central role for respiratory tract dendritic cells (RTDC) in the induction of AHR through the generation of lung-homing, allergen-specific effector T cells. We will also summarise the evidence supporting a role for regulatory T cells in the attenuation of AHR and will propose that, as a counterpoint to their capacity to induce AHR, RTDC may also play a role in the attenuation of AHR through the generation of regulatory T cells (T(reg)). A better understanding of the relationship between the physiological and immunological responses to allergen-induced AHR attenuation, and particularly the role of RTDC and T(reg) in this process, will be essential for the development of new treatments and therapies.

Airway hyperresponsiveness is associated with activated CD4+ T cells in the airways.

It is widely accepted that atopic asthma depends on an allergic response in the airway, yet the immune mechanisms that underlie the development of airway hyperresponsiveness (AHR) are poorly understood. Mouse models of asthma have been developed to study the pathobiology of this disease, but there is considerable strain variation in the induction of allergic disease and AHR. The aim of this study was to compare the development of AHR in BALB/c, 129/Sv, and C57BL/6 mice after sensitization and challenge with ovalbumin (OVA). AHR to methacholine was measured using a modification of the forced oscillation technique in anesthetized, tracheostomized mice to distinguish between airway and parenchymal responses. Whereas all strains showed signs of allergic sensitization, BALB/c was the only strain to develop AHR, which was associated with the highest number of activated (CD69(+)) CD4(+) T cells in the airway wall and the highest levels of circulating OVA-specific IgG(1). AHR did not correlate with total or antigen-specific IgE. We assessed the relative contribution of CD4(+) T cells and specific IgG(1) to the development of AHR in BALB/c mice using adoptive transfer of OVA-specific CD4(+) T cells from DO11.10 mice. AHR developed in these mice in a progressive fashion following multiple OVA challenges. There was no evidence that antigen-specific antibody had a synergistic effect in this model, and we concluded that the number of antigen-specific T cells activated and recruited to the airway wall was crucial for development of AHR.

Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells.

Understanding the mechanisms involved in respiratory tolerance to inhaled allergens could potentially result in improved therapies for asthma and allergic diseases. Airway hyperresponsiveness (AHR) is a major feature of allergic asthma, thus the aim of the current study was to investigate mechanisms underlying suppression of allergen-induced AHR during chronic allergen exposure. Adult BALB/c mice were systemically sensitized with ovalbumin (OVA) in adjuvant and then challenged with a single 3 or 6 wk of OVA aerosols. Airway and parenchymal responses to inhaled methacholine (MCh), inflammatory cell counts, cytokines, OVA-specific IgE and IgG(1), parenchymal histology, and numbers of airway CD4(+)69(+) activated and CD4(+)25(+)FoxP3(+) regulatory T (Treg) cells were assessed 24 h after the final aerosol. Single OVA challenge resulted in AHR, eosinophilia, increased serum OVA-specific IgE, and T helper 2 (Th2) cytokines in bronchoalveolar lavage (BAL) but no difference in numbers of Treg compared with control mice. Three weeks of OVA challenges resulted in suppression of AHR and greater numbers of airway Treg cells and increased transforming growth factor-beta(1) (TGFbeta(1)) compared with control mice despite the presence of increased eosinophilia, OVA-specific IgE and IgG(1), and airway remodeling. Six weeks of OVA challenges restored AHR, whereas airway Treg numbers, TGFbeta(1), BAL eosinophilia, and Th2 cytokines returned to control levels. Partial in vivo depletion or adoptive transfer of Treg cells restored or inhibited AHR, respectively, but did not affect TGFbeta(1) or Th2 cytokine production. In conclusion, AHR suppression is mediated by airway Treg cells and potentially via a paracrine induction of TGFbeta(1) in the airways.