Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only ...curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.
In Europe and the USA, at least one person in four is exposed every day to inhalant allergens of mammalian origin, a considerable number is regularly exposed for professional reasons and almost ...everyone is occasionally exposed to inhalant allergens from pets or domestic animals. The production of IgE to these inhalant allergens, often complicated by asthma and rhinitis, defines the atopic status. However, the immune response to these allergens largely imprints the cellular immune compartment and also drives non-IgE humoral immune responses in the allergic and non-allergic population. During the recent years, it has become clear that IgE antibodies recognize mammalian allergens that belong to three protein or glycoprotein families: the secretoglobins, the lipocalins, and the serum albumins. In this article, we review the humoral and cellular immune responses to the major members of these families and try to define common characteristics and also distinctive features.
Several studies have suggested that swallowing dysfunction and pulmonary aspiration occur in patients receiving prolonged ventilation. However, the incidence of swallowing dysfunction, its rate of ...resolution, and the sensitivity of tests used to characterize swallowing abnormalities are not well defined. The goals of our study were to evaluate swallowing function in this group of patients by (1) defining the specific swallowing abnormalities that occur in this patient population, (2) comparing the sensitivity of bedside evaluations to modified barium swallow with videofluoroscopy (MBS/VF), (3) performing endoscopic evaluation of the upper airway to characterize glottic function during swallowing, (4) evaluating the relationship between swallowing dysfunction and neuromuscular disorders, and (5) studying the temporal resolution of swallowing abnormalities. Swallowing function was evaluated in 35 patients receiving prolonged ventilation (ie, ≥3 weeks) admitted to a specialized rehabilitation unit dedicated to the care of patients requiring prolonged ventilation. The average age of the 35 patients was 61 ±15 years. The total duration of intubation at the time of the initial swallowing evaluation was 29 ±34 days via a cuffed tracheostomy tube and 15 ±9 days via an endotracheal tube. Neuromuscular disorders were present in 16 patients (45%). Thirty-four percent of the patients had at least one swallowing abnormality detected by bedside examination. Results of bedside swallowing examination were abnormal in 31% of patients with a neuromuscular disorder and 37% of patients without a neuromuscular disorder. MBS/VF was abnormal in 83% of patients (85% in patients with and 80% in patients without a neuromuscular disorder). Results of early (<1 month) repeated MBS/VF examinations usually remained unchanged; however, in a small group of patients, later studies (≥1 month) revealed significant improvement. In 50% of patients who underwent direct laryngoscopy, important abnormalities were found that contributed to swallowing dysfunction. Our data show that patients requiring prolonged mechanical ventilation have a high incidence of swallowing abnormalities, regardless of the presence or absence of neuromuscular disorders. MBS/VF and direct laryngoscopy can provide useful information about laryngeal action and swallowing dysfunction, and can facilitate the implementation of corrective actions to prevent respiratory complications.
Background
The prevalence of allergy to cat is expanding worldwide. Allergen‐specific immunotherapy (AIT) has advantages over symptomatic pharmacotherapy and promises long‐lasting disease control in ...allergic patients. However, there is still a need to improve cat AIT regarding efficacy, safety, and adherence to the treatment. Here, we aim to boost immune tolerance to the major cat allergen Fel d 1 by increasing the anti‐inflammatory activity of AIT with the established immunomodulatory adjuvant CpG, but at a higher dose than previously used in AIT.
Methods
Together with CpG, we used endotoxin‐free Fel d 1 as therapeutic allergen throughout the study in a BALB/c model of allergy to Fel d 1, thus mimicking the conditions of human AIT trials. Multidimensional immune phenotyping including mass cytometry (CyTOF) was applied to analyze AIT‐specific immune signatures.
Results
We show that AIT with high‐dose CpG in combination with endotoxin‐free Fel d 1 reverts all major hallmarks of allergy. High‐dimensional CyTOF analysis of the immune cell signatures initiating and sustaining the AIT effect indicates the simultaneous engagement of both, the pDC‐Treg and B‐cell axis, with the emergence of a systemic GATA3+ FoxP3hi biTreg population. The regulatory immune signature also suggests the involvement of the anti‐inflammatory TNF/TNFR2 signaling cascade in NK and B cells at an early stage and in Tregs later during AIT.
Conclusion
Our results highlight the potential of CpG adjuvant in a novel formulation to be further exploited for inducing allergen‐specific tolerance in patients with cat allergy or other allergic diseases.
AIT adjuvanted with a high and safe dose of CpG reverts major hallmarks of cat allergy without inducing any Th1/Th17 profile. The use of endotoxin‐free Fel d 1 and B‐Type CpG in AIT induces a tolerance‐promoting immune reaction through an early pDC‐NK cell‐Breg‐Treg axis, characterized by a sustained TNFR2 expression. A novel double positive FoxP3+ GATA3+ Treg subpopulation appears upon AIT.
Abbreviations: AHR, airway hyperreactivity; AIT, allergen‐specific immunotherapy; biTreg, double‐positive FoxP3+ GATA3+ Treg; CyTOF, cytometry by time‐of‐flight; CpG, oligodeoxynucleotides containing unmethylated CpG motifs; Fel d 1, Felis domesticus 1, major cat allergen; TNFR2, tumor necrosis factor receptor 2.
Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to ...imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases.
SYNOPSIS
Deficiency in a key familial Parkinson’s disease gene, PARK7/DJ‐1, reduces immunoaging in T cell compartments of both human and mice at both cellular phenotypic and functional levels.
DJ‐1 deficiency diminishes immunoaging in T cell compartments of an index PD patient.
DJ‐1 depletion reduces signs of immunoaging in murine CD8 T cells.
DJ‐1 depletion compromises OXPHOS and TCR sensitivity of naïve CD8 T cells starting at a young age, leading to relatively younger T‐cell compartments in older mice.
DJ‐1 regulates several immunoaging features via a hematopoietic‐ and naïve CD8‐T‐cell‐intrinsic manner.
Deficiency in a key familial Parkinson’s disease gene, PARK7/DJ‐1, reduces immunoaging in T cell compartments of both human and mice at both cellular phenotypic and functional levels.
Break a Habit and Save Some Bank Ventura, Maura; Leonard, Cathy; Swancer, Michelle ...
Journal of perianesthesia nursing,
August 2015, 2015-08-00, Letnik:
30, Številka:
4
Journal Article
Abstract While medications have improved the function of patients with Parkinson's disease (PD), over time most patients experience progressive problems with gait and balance. There have been ...important recent advances in the development of mechanical assistive devices that have the potential of improving mobility, but there are possible risks and the optimal role for such devices in PD has not been carefully studied. We review the available literature and provide practical information about available mobility assistive devices for patients with PD.
This thesis investigates optical feed methods for phased array antennas. The technical and practical limitations are analyzed and an optimum design is determined. This optimum optical feed is a ...two-beam interferometric approach which uses acoustooptic phase control. The theory is derived; a computer model is developed; and the limitations are determined. Design modifications are suggested which reduce limitations and greatly extend the range of applications.
Master of Science
Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a ...pacemaker regulating PDH activity in CD4
regulatory T cells (T
cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs T
survival starting in young mice and reduces T
homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible T
cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As T
homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T
homeostasis.
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