Nonhuman primate models of asthma

Asthma is a complex human disease that does not have an accurate counterpart in any common model organism. Most of our understanding of the immune mechanisms underlying asthma comes from studies in man and mouse. However, there are fundamental differences between the spontaneous disease in man and the experimentally induced counterparts in mice. We advocate more extensive use of nonhuman primate asthma models to reconcile these differences between man and mouse

A Restricted Subset of Dendritic Cells Captures Airborne Antigens and Remains Able to Activate Specific T Cells Long after Antigen Exposure

AbstractMice sensitized for a Th2 response to Leishmania LACK antigen developed allergic airway inflammation upon exposure to LACK aerosol. Using multimers of I-Ad molecules bound to a LACK peptide as probes, we tracked the migration of LACK-specific Th2 cells to the airways. Elevated numbers of LACK-specific Th2 cells remained in the airways for 5 weeks after the last aerosol. Substantial numbers of DC presenting LACK peptides were found in the airways, but not in other compartments, for up to 8 weeks after antigen exposure. These LACK-presenting airway DC expressed CD11c and CD11b as well as high levels of surface molecules involved in uptake and costimulation. Taken together, our results may explain the chronic Th2 airway inflammation characteristic of allergic asthma

Gender Differences in the Allergic Response of Mice Neonatally Exposed to Environmental Tobacco Smoke

Exposure to environmental tobacco smoke (ETS) has been shown to increase allergic sensitization and reactivity and there has been some suggestion that the influence of ETS on the allergic response is dissimilar in males and females. It is to be determined whether gender differences exist in the IgE response to ovalbumin (OVA) sensitization following ETS exposure from the neonatal period through adulthood. To address this thesis, we examined gender differences in OVA sensitization of BALB/c mice housed from birth through adulthood under smoking and nonsmoking conditions. At 6 weeks of age (day 0) all mice were injected i.p. with OVA in aluminum hydroxide adjuvant followed by three 20 min exposures to 1% aerosolized OVA between day 14 and 80. There were significantly (p<0.05) more total and OVA specific IgE and IgG1 in the serum of females compared to males. Moreover, these sex responses, along with eosinophilia, were further enhanced in mice exposed to ETS. There were also significantly more IgE positive cells in the lungs of female, but not male, mice exposed to ETS compared with ambient air (p<0.05). There was also an elevation of Th2 cytokines (IL4, IL5, IL10, and IL13) after re-stimulation of lung homogenates following ETS exposure. These data demonstrate that female animals are significantly more susceptible than males to the influence of ETS on the allergic response

T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells

CD4+CD25+ regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-β (TGF-β) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4+CD45RBhigh T cells that express a dominant negative TGF-β receptor type II (dnTβRII) and therefore cannot respond to TGF-β, escape control by T reg cells in vivo. CD4+CD25+ T reg cells from the thymus of dnTβRII mice retain the ability to inhibit colitis, suggesting that T cell responsiveness to TGF-β is not required for the development or peripheral function of thymic-derived T reg cells. In contrast, T reg cell activity among the peripheral dnTβRII CD4+CD25+ population is masked by the presence of colitogenic effector cells that cannot be suppressed. Finally, we show that CD4+CD25+ T reg cells develop normally in the absence of TGF-β1 and retain the ability to suppress colitis in vivo. Importantly, the function of TGF-β1−/− T reg cells was abrogated by anti–TGF-β monoclonal antibody, indicating that functional TGF-β can be provided by a non–T reg cell source

Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin

Cell surface heparan sulfate (HS) proteoglycans are carbohydrate-rich regulators of cell migratory, mitogenic, secretory, and inflammatory activity that bind and present soluble heparin-binding growth factors (e.g., fibroblast growth factor, Wnt, Hh, transforming growth factor β, amphiregulin, and hepatocyte growth factor) to their respective signaling receptors. We demonstrate that the deglycanated core protein of syndecan-1 (SDC1) and not HS chains nor SDC2 or -4, appears to target the epithelial selective prosecretory mitogen lacritin. An important and novel step in this mechanism is that binding necessitates prior partial or complete removal of HS chains by endogenous heparanase. This limits lacritin activity to sites where heparanase appears to predominate, such as sites of exocrine cell migration, secretion, renewal, and inflammation. Binding is mutually specified by lacritin's C-terminal mitogenic domain and SDC1's N terminus. Heparanase modification of the latter transforms a widely expressed HS proteoglycan into a highly selective surface-binding protein. This novel example of cell specification through extracellular modification of an HS proteoglycan has broad implications in development, homeostasis, and disease

Primary care research priorities in low- and middle-income countries

PURPOSE To identify and prioritize the needs for new research evidence for primary health care (PHC) in low-and middle-income countries (LMICs) about organization, models of care, and financing of PHC. METHODS Three-round expert panel consultation of LMIC PHC practitioners and academics sampled from global networks, via web-based surveys. Iterative literature review conducted in parallel. Round 1 (pre–Delphi survey) elicited possible research questions to address knowledge gaps about organization and models of care and about financing. Round 2 invited panelists to rate the importance of each question, and in round 3 panelists provided priority ranking. RESULTS One hundred forty-one practitioners and academics from 50 LMICs from all global regions participated and identified 744 knowledge gaps critical to improving PHC organization and 479 for financing. Four priority areas emerged: effective transition of primary and secondary services, horizontal integration within a multidisciplinary team and intersectoral referral, integration of private and public sectors, and ways to support successfully functioning PHC professionals. Financial evidence priorities were mechanisms to drive investment into PHC, redress inequities, increase service quality, and determine the minimum necessary budget for good PHC. CONCLUSIONS This novel approach toward PHC needs in LMICs, informed by local academics and professionals, created an expansive and prioritized list of critical knowledge gaps in PHC organization and financing. It resulted in research questions, offering valuable guidance to global supporters of primary care evaluation and implementation. Its source and context specificity, informed by LMIC practitioners and academics, should increase the likelihood of local relevance and eventual success in implementing research findings