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Hindawi Publishing Corporation Journal of Allergy Volume 2012, Article ID 176468, 10 pages doi:10.1155/2012/176468 Review Article Lung Dendritic Cell Developmental Programming, Environmental Stimuli, and Asthma in Early Periods of Life 1 1 2 3 Shanjana Awasthi, Bhupinder Singh, Robert C. Welliver, and Rodney R. Dietert Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA Correspondence should be addressed to Shanjana Awasthi, firstname.lastname@example.org Received 1 June 2012; Revised 29 September 2012; Accepted 30 September 2012 Academic Editor: Hamida Hammad Copyright © 2012 Shanjana Awasthi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dendritic cells (DCs) are important cells of our innate immune system. Their role is critical in inducing adaptive immunity, tolerance, or allergic response in peripheral organs—lung and skin. The lung DCs are not developed prenatally before birth. The DCs develop after birth presumably during the ﬁrst year of life; exposures to any foreign antigen or infectious organisms during this period can signiﬁcantly aﬀect DC developmental programming and generation of distinct DC phenotypes and functions. These changes can have both short-term and long-term health eﬀects which may be very relevant in childhood asthma and predisposition for a persistent response in adulthood. An understanding of DC development at molecular and cellular levels can help in protecting neonates and infants against problematic environmental exposures and developmental immunotoxicity. This knowledge can eventually help in designing novel pharmacological modulators to skew the DC characteristics and immune responses to beneﬁt the host across a lifetime. 1. Introduction sensitization, the antigen presenting cells (dendritic cells— DCs, macrophages, and lung epithelial cells) take up and process the inhalant allergens. The DCs are recognized as the Asthma is a serious pulmonary disease that aﬀects about 300 million people worldwide , and 8.2% (about 25 key immune sentinel cell in the peripheral organs, including million) of the population within the USA . A signiﬁcant lung , and are at the cross-roads of inducing tolerance or inﬂammation . The DCs are activated directly or number of patients develop asthma during early childhood. A number of cross-sectional and longitudinal cohort studies via cell-cell interaction . The activated DCs in turn stimulate T and B cells and other immune cells, which in adult asthmatic patients suggest that the childhood asthma poses a risk for more severe asthma or relapse during adult- release a variety of cytokines, chemokines, and chemical hood [3–6]. One among ten children has asthma, and this mediators. These mediators are responsible for aﬀecting the local microenvironment and generating inﬂammation trend has increased over the recent years . Characteristics (airway obstruction, airway hyperresponsiveness, atopy, and and obstruction in airways. Traditionally, asthma has been recent wheeze)observedinchildrenhavebeenreportedas known as the Th2-mediated disease (Figure 1). Both Th2- and non-Th2-dependent immune elements and mechanisms predictors of asthma symptoms in adulthood. This is sup- ported by evidence that the sensitization to allergens at young are now recognized for a number of phenotypes and endo- types of asthma [15–17]. age increases the likelihood of asthma in adulthood [8–11]. In allergic asthma, an immune reaction is caused by While asthma phenotypes and endotypes are not fully inhaled allergens with an overwhelming inﬂammatory characterized, resident lung DC types could be important [12, 18–22]. Lung DCs exhibit unique phenotypes than response and obstruction in the airways. As a ﬁrst step in 2 Journal of Allergy Antigen Antigen presenting cell Antigen Antigen (macrophage, DCs) Mast cell FcεR IgE activation production Processed IgE Antigen Mast antigen presentation cell IL-4, IL-13 Th2 B cell cell IL-4, IL-5, IL-6 Release of mediators, inﬂammatory cell activation, asthma Figure 1: An illustration depicting the types of immune cells involved in a Th2-mediated allergic response. Antigen presenting cells (macrophages or DCs) take up the antigen, process it, and present it on the MHC molecule on the cell surface. The antigen presenting cells induce na¨ıve T cells towards Th1 or Th2. Th2 response is mainly responsible for downstream events that include activation of B cells, production of IgE, and binding of IgE to Fcε receptor on the cell surface of mast cells, resulting into mast cell degranulation and inﬂammation. those present in other organs or in circulation , and of immune vulnerability” have the potential to program are distributed throughout the alveolar epithelium, alveolar DC types, DC functions, and DC-mediated tolerance or parenchyma, and nasal mucosa [24, 25]. A variety of sensitization, which can have long-term respiratory and investigations in rodents and human patients have reported immunological consequences (Figure 2)[32, 39, 40]. the importance of diﬀerent lung DC types in asthma [26–29]. This corresponds with the reported results on alterations in 3. Developing Immune System and selective DC populations in the bronchoalveolar lavage ﬂuids Exposure to Asthma-Triggering Agents in (BALFs) and in peripheral blood of patients with asthma Early Childhood (Table 1). A number of distinctive reports are available in the literature on the characteristics and functions of lung DC Particular events during early childhood can set the stage for types [23, 30, 31], and are not reviewed here. In this paper, speciﬁc developmental programming of DCs. The ﬂexibility we provide an overview of lung DC development, exposure of a developing immune system and simultaneous exposure to pathogens, allergens, and environmental chemicals during to allergens and other environmental stimuli can be impor- early childhood, and their long-term impact on asthma tant compounding factors for both the establishment and a development. long-term persistence of asthma. In addition to allergens, other risk factors for DC devel- opmental programming towards particular DC phenotype 2. Critical Window of Immune Vulnerability and function during this “critical window period” may Over the last several years, prominent research studies have include environmental chemicals, drugs, certain dietary fac- demonstrated that the late fetal and early postnatal periods tors, infectious agents, and physical and psychological are phases of reduced immune competence [12, 32, 33]. This stressors. Not surprisingly, research studies suggest that the reported reduced immune competence corresponds with the maturation and function of DCs are shifted by some of these immaturity of immune system. In particular, the lung DCs predisposing risk factors. These include heavy metals, such are underdeveloped prenatally and close to term at birth [18, as lead , and air pollutants particularly those from traﬃc 34–38]. The development of lung DCs during infanthood  and environmental tobacco smoke . Among rele- has not been studied. Concurrent exposures to allergens and vant shifts that have been reported are: (1) reduced expres- other environmental factors during this “critical window sion of Toll-like receptors (TLR)2 and TLR4 , (2) shift to Journal of Allergy 3 Table 1: DC subsets in patients with asthma. Clinical Condition Altered DC phenotypes References pDC (HLA-DR+, CD123+) increased in BALF Asthma  mDC (HLA-DR+, CD11c+) increased in BALF Allergic asthma mDC (BDCA-3+, mannose receptor+) increased in BALF  pDC (BDCA4+) with increased FcεRI in blood Allergic asthma [101, 102] mDC (CD1c+) with increased FcεRI in blood Asthma Increased DC proportions in peripheral blood  Allergic asthma patients challenged with allergen Increased pDC and mDC in sputum  Asthma Increase in pDC1 and pDC2 expressing FcεRI  Repeated exposure to allergen Depletion of mDCs  Asthmatic children DC2 (CD11c−, CD123high+) decreased in blood  Asthmatic patients  Increased CD1a+ cells in bronchial mucosa Experimentally elicited allergic rhinitis  pDC increased in nasal mucosa Asthma  pDC increased; decreased mDC : pDC ratio in blood Children with asthma  Deﬁciency of circulating pDC Atopic patients with chronic rhinosinusitis  Increased FcεRI on DC (CD1+) Abbreviations: BALF: bronchoalveolar lavage ﬂuid, mDC: myeloid DC, pDC: plasmacytoid DC, BDCA: blood dendritic cell antigen. Conception Birth 2 years Critical window of immune vulnerability ? ? Development of lung DCs ? Development of macrophage responses Maturation of BALT, GALT, and T cells (a) Fetal to Early childhood Close to birth Birth ? ? ? Lung microenvironment, Stem DC precursor developmental signal, and Lung DCs environmental exposure cells (SDPCs) (b) Figure 2: Immune development during critical window of vulnerability. (a) Timeline of maturation of bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT), T cells, and macrophages. (b) Lung-resident SDPCs could be the plausible source of lung DCs in early childhood. The timing of lung DC development, environmental factors triggering this transition, and signaling mechanisms involved in DC development remain unknown. Th2-biased adaptive immune response , and (3) promo- hypothesis” have been discussed elsewhere in the literature tion of misregulated (unresolved) inﬂammation [46, 47]. for controlling asthma-related immune response [54, 55]. A number of recent studies have demonstrated that early exposures to Chlamydia muridarum (an intracellular pathogen) [48–50], Bacillus Calmette-Guer ´ in (BCG) , 4. Respiratory Syncytial Virus (RSV) and inﬂuenza A virus  alter the immune responses Infection and Asthma against allergens in adulthood via aﬀecting the DC types and functions. Bacterial infections or stimulation with TLR4 Respiratory syncytial virus infection is the most common ligand (Gram-negative bacteria-derived lipopolysaccharide) cause of bronchiolitis and pneumonia in children under 1 have been shown to skew the T-cell response to Th1 type dur- year of age (Centers for Disease Control and Prevention, ing childhood . In this regard, “Probiotics” and “Hygiene Atlanta, GA, USA). Severe forms of the RSV lower respiratory 4 Journal of Allergy tract infections (LRTI) are characterized by airway obstruc- the immune responses to RSV and airway reactivity follow- tion and prominent wheezing. Furthermore, RSV infection ing RSV infection . The recruitment and activity of DC subsets occurring after RSV infection could skew immune in infancy has been linked to the development of asthma in childhood. Thus, there has been great interest in determining responses toward either Th1 or Th2 cytokine pathways, thereby determining the eventual development of atopic whether the pathogenesis of RSV bronchiolitis in infancy disease or long-term airway hyperreactivity following RSV induces a persistent Th2 bias, leading to the development of infection in infancy. Th2-dependent asthma in later childhood. Some studies have focused on the expression of the pro- totype Th1 cytokine, interferon gamma (IFN-γ), and the 5. Lung DC Development Th2 cytokine, interleukin-4 (IL-4). Bendelja and colleagues studied the expression of IFN-γ and IL-4 in peripheral Despite growing understanding about the DC characteristics and functions in adult patients and animal models, the natu- blood lymphocytes (PBL) of infants with various forms of RSV infection . Among RSV-infected infants, the ral processes of lung DC development in prenatal or neonatal phase, as well as diﬀerentiation, maturation, and functional percentage of PBL positive for IL-4 was slightly greater than specialization of DCs, have not yet been studied. An under- the percentage positive for IFN-γ,thussuggesting aTh2 standing of perinatal and infant DC maturation in environ- bias. However, the expression of IL-4 was greater in subjects mentally exposed tissues (including lung) is critical to better with mild upper respiratory tract infection (URTI) than in manage immune maturation for a healthier life course. subjects with bronchiolitis or pneumonia. IFN-γ expression Histological details reveal that the MHC class II-positive remained unaﬀected. Therefore, patterns of IFN-γ and IL-4 cells start to appear in lung tissues of rat and human fetuses expression by PBL could not be associated with the severity at 30–58% of term. Since the MHC class II is expressed of RSV infection. ubiquitously by a variety of immune and nonimmune cells, Others have determined the quantities of IFN-γ and the interpretation may not be DC speciﬁc. The appearance IL-4 cytokines in respiratory tract secretions of infants of MHC class II-positive DCs increases only after birth with RSV infections. In one study, IFN-γ was found to be [37, 67–70]. the predominant cytokine in subjects with all forms of Importantly, the airway structures and epithelial cell sys- respiratory tract illness related to RSV infection, with slightly tem are also not fully developed at the time of birth or during higher ratios of IFN-γ to IL-4 in those with LRTI in the neonatal period. It is reasonable to believe that direct cell- comparison to those with URTI alone . A second, larger cell interaction or chemical mediators and growth factors study similarly demonstrated that the Th2 cytokines, IL-4, released by another cell type can have a signiﬁcant impact IL-5, and IL-13, were usually undetectable in secretions from on the establishment of normal lung DC infrastructure as infants with all forms of RSV infection. IFN-γ appeared to be the lung microenvironment and the normal lung physiology protective against severe illness, in that IFN-γ concentrations evolve [13, 71, 72]. Repeated exposure to potentially harmful were greater in subjects with milder, nonhypoxic forms allergens or other environmental stimuli during this period of RSV-induced LRTI than in those with more severe can signiﬁcantly aﬀect the DC programming, phenotypes, LRTI accompanied by hypoxia . In all of these studies, and functions. Although it remains to be studied, these the diﬀerences in ratios of IFN-γ to Th2 cytokines were events may prompt a long-term memory for the generation determined only by variations in IFN-γ concentrations of asthma-promoting DCs. between the groups. The ﬁndings of subsequent studies have also suggested a protective role for IFN-γ in RSV infection of infants [59, 60]. 6. Animal Models for Studying Lung How the DC phenotypes and DC-induced T-cell DC Development responses are skewed following RSV infection is an impor- tant question, and could provide clues to the severity of the Technical and ethical issues related to the availability of disease and predisposition to asthma. Infection of human neonatal and infant lung tissues limit the enthusiasm to infants with RSV and other viruses is followed by the conduct studies that address the issues related to lung DC appearance of DCs in nasopharyngeal and tracheal secretions development. Studies are limited to ﬁrst challenging the [61, 62]. RSV infection of monocyte-derived DCs causes neonatal animal with infectious or allergenic stimuli and maturation of the cells, with expression of costimulatory then investigating the DC types and functions later in life in molecules that participate in the instruction of T cells. the same animal. This approach may not adequately reﬂect However, it results in impaired CD4-positive T cells . the dynamic process of DC development or programming Although DC types were not addressed, the lung tissues from during early childhood in humans. Since DCs make <1% of infants with fatal RSV demonstrated a lack of CD8−positive total lung cells , it is not possible to harvest suﬃcient T cells . Studies in mice have suggested unique roles DC populations from rodent pups because of their small- for myeloid (mDC) and plasmacytoid DCs (pDC) in RSV sized lung. Hundreds of small-sized, age-matched mouse infection. The pDCs in RSV-infected mice reduce the viral pups (most commonly used model) would be needed to replication, while depletion of pDCs results in enhanced harvest an adequate number of cells; it is almost impossible inﬂammatory responses and greater airway hyperreactivity to have simultaneous births and enough age-matched mouse . A balance between mDC and pDC seems to determine progeny available for this purpose. Also, the cells cannot be Journal of Allergy 5 pooled from pups born close together, because murine pups adult human lung ; their diﬀerentiation into lung DC- (between birth and one-month) age at 150 times faster rate precursors or DCs has not yet been studied. than humans . There are signiﬁcant diﬀerences in the lung anatomical , developmental, and immunological 7. Molecular and Immunologic Basis for aspects of humans and mice (e.g., the lymphocyte and DC Programming and neutrophil distribution in blood, DC phenotypes) which Therapeutic Opportunities make it diﬃcult to interpret and translate the results to human infants [75–77]. As such, murine DC precursors/DC In summary, our results indicate that the lung DCs are not phenotypes are diﬀerent from those reported in humans developed at least until birth. We do not know when the DCs [23, 78]. Cellular intermediates within the hematopoietic develop after birth during childhood, what triggers the lung stem cell hierarchy tree have been identiﬁed in tissues of DC development, and how the pathogenic stimuli aﬀect the mice and humans [79, 80]; signiﬁcant diﬀerences have been DC development leading to DC phenotypes with diﬀerent noted in regards to their subsets and frequency . Lack functions. We speculate that pathogenic stimuli, such as of reagents and paucity of information on DC-precursors or allergens, may alter the lung DC developmental program- DCs limit such studies in other rodents. These studies are ming or SDPC→DC transition during early childhood in a also not possible in human neonates or infants due to ethical way that an immunological memory is created for generation reasons. Large animal models are expensive and require of asthma-promoting DC phenotypes or immune responses. diligent work; these models can mimic the conditions of Persistent reexposure to allergens may bolster the generation human infants very closely. To this eﬀect, an asthma model is of these DC phenotypes so that an allergic response is available in Rhesus monkeys. Similarities have been reported maintained for a long time. in asthmatic response among Rhesus monkeys and humans; An understanding of the basic immunobiology of the house dust mite antigen induces asthma conditions with DC development and the early programming of asthma- clinical proﬁles; the biochemical and immunological markers promoting DC phenotypes and functions against allergenic are similar to those in human patients of asthma [74, 81, 82]. stimuli can pave the way to identify the basis of childhood The baboon model seems ideal for studying the early asthma. Although it can be challenging to study the molec- human immune maturation and the developmental pro- ular mechanisms for lung DC development in vivo, studies gramming  because of similarities in ontogeny, immu- with baboon lung SDPCs and DCs can provide useful tools nology, reproductive physiology, placentation, and maternal- to unravel the molecular and immunologic basis of the fetal transfer [84–88]. They are very close to humans in the lung DC development and develop novel pharmacological evolutionary tree , and the lung development pattern in modulators. A focused eﬀort in this direction can provide preterm baboons is similar to that found in preterm human a unique opportunity to eﬀectively manage the pediatric babies . Some of the immunological aspects [91–93], immune system for optimized maturation and reduced the bronchoconstriction, and the airway response against health risks. This would include opportunities to intervene at platelet-activating factor  in baboons are also analogous an early age and skew the DC programming towards normal to those of humans and asthmatic patients, respectively. DC phenotype and function using pharmacological modu- The advantages of the baboon over other commonly used lators. Additionally, this information may be useful in better primates, such as Rhesus monkey, include the ease of timed protecting neonates and infants from environmental insults pregnancies due to the estrogen-sensitive sex skin in cycling that increase the later-life health risks. It is the magnitude and females, the availability (baboons breed year-round), and persistence of downstream immunoinﬂammatory eﬀects of the relative ease of handling (reviewed in ). Moreover, tissue DC function that position this topic as a central health it allows harvesting of suﬃcient number of cells of interest issue for allergic and other chronic diseases. from relatively large tissues of neonate and infant baboons. We have studied the development of pulmonary innate immunity, including DCs, in a non human primate baboon Funding (Papio species) model [34, 35, 95–97]. We have investigated Funding was provided by the American Lung Association the DC phenotypes and functions in prematurely delivered and Presbyterian Health Foundation to S. Awasthi for con- and close-to-term baboons (67–95% of gestation). Our ducting related studies in baboons. results demonstrate that lung DC population having low density (similar to those of adult baboon lung DC popula- tion) remains underdeveloped until close to birth . Since Authors’ Contribution we do not know the stage of diﬀerentiation and the cell subsets, it is probably more appropriate to call them stem All authors have contributed and reviewed the paper. Speciﬁc DC precursor cells (SDPCs) . We have recently observed contributions by the authors are as follows: B. Singh that the SDPCs can diﬀerentiate into DCs in vitro under compiled Table 1 in the paper. R. C. Welliver and R. R. DC-promoting conditions (Figure 3). A signiﬁcant increase Dietert contributed to the text related to RSV, critical window in expression of DC markers and tentacles is observed over of immune vulnerability, and environmental exposures, time. It has been proposed by others that the tissue DCs respectively. S. Awasthi conducted studies related to the can be generated from hitherto unknown resident stem cell baboon DCs in her lab and coordinated with co-authors for populations. Isolation of stem cells has been reported from compilation of this paper. 6 Journal of Allergy Day 3 Day 11 ∗ ∗ (a) HLA-DP, CD11c CD40 CD80 CD86 DQ, DR (b) Markers HLA- CD11c CD40 CD80 CD86 DP, DQ, DR Days in culture Isotype control 4.4% (160) 9% (148) 4.4% (160) 9% (148) 5.3% (79) 6 days 30% (366) 19% (355) 10% (280) 28% (1601) 39% (328) 11 days 37% (629) 44% (322) 26% (382) 54% (1049) 61% (295) 17 days 41% (617) 34% (355) Not done Not done Not done (c) Figure 3: The SDPCs harvested from a close-to-term fetal baboon diﬀerentiate into DCs when cultured in presence of GM-CSF, IL-4, and TNF-α. The lung SDPCs were harvested on OptiPrep density gradient as per the method published earlier . (a) Photomicrograph showing cells with dendrites ( ). (b) Flow cytometry data showing increase in DC-marker expression. Black line: isotype control antibody- stained cells, green line: 6 days, blue line: 11 days, red line: 17 days—cells stained with antibodies to particular marker. (c) Data in the table shows % cells (ﬂuorescent intensity) gated in the marked region of histogram charts in (b) staining positive for the speciﬁc marker. Acknowledgments  L. Duijts, “Fetal and infant origins of asthma,” European Jour- nal of Epidemiology, vol. 27, no. 1, pp. 5–14, 2012. The authors acknowledge the Baboon Research Resources  B. Brunekreef, E. Von mutius, G. K. Wong, J. A. Odhiambo, at the University of Oklahoma Health Sciences Center, and T. O. Clayton, “Early life exposure to farm animals and Oklahoma City, OK, USA, and Baboon resource programs at symptoms of asthma, rhinoconjunctivitis and eczema: an the University of Texas Health Sciences Center and Southwest ISAAC phase three study,” International Journal of Epidemi- ology, vol. 41, no. 3, pp. 753–761, 2012. Foundation for Biomedical Research, San Antonio, TX, USA,  L. Akinbami, “The state of childhood asthma, United States, for providing baboon tissues and ﬂuid specimens. 1980–2005,” Advance data, no. 381, pp. 1–24, 2006.  B. G. Toelle, W. Xuan, J. K. Peat, and G. B. Marks, “Childhood References factors that predict asthma in young adulthood,” European Respiratory Journal, vol. 23, no. 1, pp. 66–70, 2004.  World Health Organization, Global Surveillance, Prevention  C. Almqvist, Q. Li, W. J. Britton et al., “Early predictors for and Control of Chronic Respiratory Diseases: A Comprehensive developing allergic disease and asthma: examining separate Approach, 2007. steps in the ‘allergic march’,” Clinical and Experimental  National Center for Health Statistics, 2012, http://www.cdc Allergy, vol. 37, no. 9, pp. 1296–1302, 2007. .gov/nchs/data/nhsr/nhsr032.pdf.  T. Schafer ¨ , G. Wolk ¨ e, J. Ring, H. E. Wichmann, and J.  C. Seg ´ ala, G. Priol, D. Soussan et al., “Asthma in adults: com- Heinrich, “Allergic sensitization to cat in childhood as major parison of adult-onset asthma with childhood-onset asthma predictor of incident respiratory allergy in young adults,” relapsing in adulthood,” Allergy, vol. 55, no. 7, pp. 634–640, Allergy, vol. 62, no. 11, pp. 1282–1287, 2007.  M. R. Sears, J. M. Greene, A. R. Willan et al., “A longitudinal,  L. M. Taussig, A. L. Wright, C. J. Holberg, M. Halonen, W. J. population-based, cohort study of childhood asthma fol- Morgan, and F. D. Martinez, “Tucson Children’s respiratory study: 1980 to present,” Journal of Allergy and Clinical Immu- lowed to adulthood,” The New England Journal of Medicine, vol. 349, no. 15, pp. 1414–1422, 2003. nology, vol. 111, no. 4, pp. 661–675, 2003. Journal of Allergy 7  P. G. Holt and P. D. Sly, “Prevention of allergic respiratory asthma as a paradigm,” Journal of Aerosol Medicine, vol. 15, disease in infants: current aspects and future perspectives,” no. 2, pp. 161–168, 2002. Current Opinion in Allergy and Clinical Immunology, vol. 7,  M. A. Gill, “The role of dendritic cells in asthma,” Journal of no. 6, pp. 547–555, 2007. Allergy and Clinical Immunology, vol. 129, no. 4, pp. 889–901,  B. N. Lambrecht and H. Hammad, “The role of dendritic and epithelial cells as master regulators of allergic airway inﬂam-  R. R. Dietert and J. T. Zelikoﬀ, “Early-life environment, dev- elopmental immunotoxicology, and the risk of pediatric alle- mation,” The Lancet, vol. 376, no. 9743, pp. 835–843, 2010. rgic disease including asthma,” Birth Defects Research Part B,  B. N. Lambrecht and H. Hammad, “The other cells in asth- vol. 83, no. 6, pp. 547–560, 2008. ma: dendritic cell and epithelial cell crosstalk,” Current Opin-  P. G. Holt and P. D. Sly, “Prevention of adult asthma by ion in Pulmonary Medicine, vol. 9, no. 1, pp. 34–41, 2003. early intervention during childhood: potential value of new  S. Wenzel, “Severe asthma: from characteristics to pheno- generation immunomodulatory drugs,” Thorax, vol. 55, no. types to endotypes,” Clinical and Experimental Allergy, vol. 8, pp. 700–703, 2000. 42, no. 5, pp. 650–658, 2012.  S. Awasthi, R. Wolf, and G. White, “Ontogeny and phagocytic  N. R. Bhakta and P. G. Woodruﬀ, “Human asthma phe- function of baboon lung dendritic cells,” Immunology and notypes: from the clinic, to cytokines, and back again,” Cell Biology, vol. 87, no. 5, pp. 419–427, 2009. Immunological Reviews, vol. 242, no. 1, pp. 220–232, 2011.  S. Awasthi and J. Cropper, “Immunophenotype and func-  S. E. Wenzel, “Asthma phenotypes: the evolution from tions of fetal baboon bone-marrow derived dendritic cells,” clinical to molecular approaches,” Nature Medicine, vol. 18, Cellular Immunology, vol. 240, no. 1, pp. 31–40, 2006. no. 5, pp. 716–725, 2012.  S. Awasthi, R. Madhusoodhanan, and R. Wolf, “Surfactant  P. G. Holt, “Dendritic cell ontogeny as an aetiological factor protein-A and toll-like receptor-4 modulate immune func- in respiratory tract diseases in early life,” Thorax, vol. 56, no. tions of preterm baboon lung dendritic cell precursor cells,” 6, pp. 419–420, 2001. Cellular Immunology, vol. 268, no. 2, pp. 87–96, 2011.  P. G. Holt, C. Macaubas, S. L. Prescott, and P. D. Sly, “Micro-  T. Tschernig,V.C.DeVries,A.S.Debertinetal., “Density bial stimulation as an aetiologic factor in atopic disease,” of dendritic cells in the human tracheal mucosa is age Allergy, vol. 54, supplement 49, pp. 12–16, 1999. dependent and site speciﬁc,” Thorax, vol. 61, no. 11, pp. 986–  P. G. Holt, J. Oliver, N. Bilyk et al., “Downregulation of the 991, 2006. antigen presenting cell function(s) of pulmonary dendritic  T. Tschernig, A. S. Debertin, F. Paulsen, W. J. Kleemann, and cells in vivo by resident alveolar macrophages,” The Journal R. Pabst, “Dendritic cells in the mucosa of the human trachea of Experimental Medicine, vol. 177, no. 2, pp. 397–407, 1993. are not regularly found in the ﬁrst year of life,” Thorax, vol.  P. G. Holt and J. W. Upham, “The role of dendritic cells in 56, no. 6, pp. 427–431, 2001. asthma,” Current Opinion in Allergy and Clinical Immunol-  R. R. Dietert, “Developmental immunotoxicity (DIT) in ogy, vol. 4, no. 1, pp. 39–44, 2004. drug safety testing: matching DIT testing to adverse out-  A. Rate,J.W.Upham,A.Bosco,K.L.McKenna,and P. G. comes and childhood disease risk,” Current Drug Safety, vol. Holt, “Airway epithelial cells regulate the functional pheno- 3, no. 3, pp. 216–226, 2008. type of locally diﬀerentiating dendritic cells: implications for  R. R. Dietert and M. S. Piepenbrink, “The managed immune the pathogenesis of infectious and allergic airway disease,” system: protecting the womb to delay the tomb,” Human and Journal of Immunology, vol. 182, no. 1, pp. 72–83, 2009. Experimental Toxicology, vol. 27, no. 2, pp. 129–134, 2008.  M. H. Grayson, “Lung dendritic cells and the inﬂammatory  D. Gao, T. K. Mondal, and D. A. Lawrence, “Lead eﬀects response,” Annals of Allergy, Asthma and Immunology, vol. 96, on development and function of bone marrow-derived no. 5, pp. 643–651, 2006. dendritic cells promote Th2 immune responses,” Toxicology  B. J. Masten and M. F. Lipscomb, “Methods to isolate and Applied Pharmacology, vol. 222, no. 1, pp. 69–79, 2007. and study lung dendritic cells,” in Lung Macrophages and  M. Porter, M. Karp, S. Killedar et al., “Diesel-enriched Dendritic Cells in Health and Disease, M. F. Lipscomb and S. particulate matter functionally activates human dendritic W. Russell, Eds., pp. 223–238, Marcel Dekker, New York, NY, cells,” American Journal of Respiratory Cell and Molecular USA, 1997. Biology, vol. 37, no. 6, pp. 706–719, 2007.  A. S. McWilliam and P. G. Holt, “Immunobiology of den-  D. Gentile, J. Howe-Adams, J. Trecki, A. Patel, B. Angelini, dritic cells in the respiratory tract: steady-state and inﬂam- and D. Skoner, “Association between environmental tobacco matory sentinels?” Toxicology Letters, vol. 102-103, pp. 323– smoke and diminished dendritic cell interleukin 10 pro- 329, 1998. duction during infancy,” Annals of Allergy, Asthma and  B. N. Lambrecht, “Lung dendritic cells: from basic physiolo- Immunology, vol. 92, no. 4, pp. 433–437, 2004. gyto clinical applications,” Acta Clinica Belgica,vol. 62, no.5,  M. A. Williams, C. Cheadle, T. Watkins et al., “TLR2 and pp. 330–334, 2007. TLR4 as potential biomarkers of environmental particulate  B. Lambrecht and H. Hammad, “Lung dendritic cells: targets matter exposed human myeloid dendritic cells,” Biomark for therapy in allergic disease,” Chemical Immunology and Insights, vol. 2, pp. 226–240, 2007. Allergy, vol. 94, pp. 189–200, 2008.  G. F. G. Bezemer, S. M. Bauer, G. Oberdorst ¨ er et al., “Acti-  B. N. Lambrecht and H. Hammad, “Biology of lung dendritic vation of pulmonary dendritic cells and Th2-type inﬂamma- cells at the origin of asthma,” Immunity,vol. 31, no.3,pp. tory responses on instillation of engineered, environmental 412–424, 2009. diesel emission source or ambient air pollutant particles in  C. J. Suarez, N. J. Parker, and P. W. Finn, “Innate immune vivo,” Journal of Innate Immunity, vol. 3, no. 2, pp. 150–166, mechanism in allergic asthma,” Current Allergy and Asthma Reports, vol. 8, no. 5, pp. 451–459, 2008.  M. A. Williams, T. Rangasamy, S. M. Bauer et al., “Disruption  P. G. Holt, “The role of airway dendritic cell populations of the transcription factor Nrf2 promotes pro-oxidative den- in regulation of T-cell responses to inhaled antigens: atopic dritic cells that stimulate Th2-like immunoresponsiveness 8 Journal of Allergy upon activation by ambient particulate matter,” Journal of respiratory infections,” Journal of Infectious Diseases, vol. 191, Immunology, vol. 181, no. 7, pp. 4545–4559, 2008. no. 7, pp. 1105–1115, 2005.  H. Renz, P. Brandtzaeg, and M. Hornef, “The impact of  M. A. Gill, K. Long, T. Kwon et al., “Diﬀerential recruitment perinatal immune development on mucosal homeostasis and of dendritic cells and monocytes to respiratory mucosal sites chronic inﬂammation,” Nature Reviews Immunology, vol. 12, in children with inﬂuenza virus or respiratory syncytial virus no. 1, pp. 9–23, 2012. infection,” Journal of Infectious Diseases, vol. 198, no. 11, pp. 1667–1676, 2008.  L. Jiao, X. Han, S. Wang et al., “Imprinted DC mediate the immune-educating eﬀect of early-life microbial exposure,”  P. M. A. De Graaﬀ,E.C.DeJong, T. M. VanCapel et al., European Journal of Immunology, vol. 39, no. 2, pp. 469–480, “Respiratory syncytial virus infection of monocyte-derived 2009. dendritic cells decreases their capacity to activate CD4 T  M. R. Starkey, R. Y. Kim, E. L. Beckett et al., “Chlamydia mur- cells,” Journal of Immunology, vol. 175, no. 9, pp. 5904–5911, idarum lung infection in infants alters hematopoietic cells to promote allergic airway disease in mice,” PLoS ONE, vol. 7,  T. P. Welliver, R. P. Garofalo, Y. Hosakote et al., “Severe no. 8, Article ID e42588, 2012. human lower respiratory tract illness caused by respiratory syncytial virus and inﬂuenza virus is characterized by the  E. L. Beckett, S. Phipps, M. R. Starkey et al., “TLR2, but not TLR4, is required for eﬀective host defence against absence of pulmonary cytotoxic lymphocyte responses,” Journal of Infectious Diseases, vol. 195, no. 8, pp. 1126–1136, Chlamydia respiratory tract infection in early life,” PLoS ONE, vol. 7, no. 6, Article ID e39460, 2012. 2007.  X. Roux, A. Remot, A. Petit-Camurdan et al., “Neonatal lung  H. Wang, N. Peters, and J. Schwarze, “Plasmacytoid dendritic immune responses show a shift of cytokines and transcrip- cells limit viral replication, pulmonary inﬂammation, and tion factors toward Th2 and a deﬁcit in conventional and airway hyperresponsiveness in respiratory syncytial virus infection,” Journal of Immunology, vol. 177, no. 9, pp. 6263– plasmacytoid dendritic cells,” European Journal of Immunol- ogy, vol. 41, no. 10, pp. 2852–2861, 2011. 6270, 2006.  A. Al-Garawi, R. Fattouh, F. Botelho et al., “Inﬂuenza A facil-  J. J. Smit, D. M. Lindell, L. Boon, M. Kool, B. N. Lambrecht, itates sensitization to house dust mite in infant mice leading and N. W. Lukacs, “The balance between plasmacytoid DC to an asthma phenotype in adulthood,” Mucosal Immunology, versus conventional DC determines pulmonary immunity to vol. 4, no. 6, pp. 682–694, 2011. virus infections,” PLoS ONE, vol. 3, no. 3, Article ID e1720,  H. Renz, “Asthma protection with bacteria—science or ﬁction?” Thorax, vol. 66, no. 9, pp. 744–745, 2011.  D. J. Nelson, C. McMenamin, A. S. McWilliam, M. Brenan, and P. G. Holt, “Development of the airway intraepithelial  P. G. Holt, D. H. Strickland, and P. D. Sly, “Virus infection dendritic cell network in the rat from class II major histo- and allergy in the development of asthma: what is the con- compatibility (Ia)-negative precursors: diﬀerential regulation nection?” Current Opinion in Allergy and Clinical Immunol- of Ia expression at diﬀerent levels of the respiratory tract,” ogy, vol. 12, no. 2, pp. 151–157, 2012. The Journal of Experimental Medicine, vol. 179, no. 1, pp.  T. Brar, S. Nagaraj, and S. Mohapatra, “Microbes and asthma: 203–212, 1994. the missing cellular and molecular links,” Current Opinion in  K. Hamada, C. A. Goldsmith, A. Goldman, and L. Kobzik, Pulmonary Medicine, vol. 18, no. 1, pp. 14–22, 2012. “Resistance of very young mice to inhaled allergen sensitiza-  K. Bendelja, A. Gagro, A. Bace et al., “Predominant type- tion is overcome by coexposure to an air-pollutant aerosol,” 2 response in infants with respiratory syncytial virus (RSV) American Journal of Respiratory and Critical Care Medicine, infection demonstrated by cytokine ﬂow cytometry,” Clinical vol. 161, no. 4, part 1, pp. 1285–1293, 2000. and Experimental Immunology, vol. 121, no. 2, pp. 332–338, 2000.  F. M. Hofman, J. A. Danilovs, and C. R. Taylor, “HLA-DR (Ia)-positive dendritic-like cells in human fetal nonlymphoid  S. M. Van Schaik, D. A. Tristram, I. S. Nagpal, K. M. Hintz, R. tissues,” Transplantation, vol. 37, no. 6, pp. 590–594, 1984. C. Welliver, and R. C. Welliver, “Increased production of IFN- γ and cysteinyl leukotrienes in virus- induced wheezing,”  K. M. McCarthy,J.L.Gong, J. R. Telford, andE.E.Schnee- berger, “Ontogeny of Ia+ accessory cells in fetal and newborn Journal of Allergy and Clinical Immunology, vol. 103, no. 4, pp. 630–636, 1999. rat lung,” American Journal of Respiratory Cell and Molecular Biology, vol. 6, no. 3, pp. 349–356, 1992.  R. P. Garofalo, J. Patti, K. A. Hintz, V. Hill, P. L. Ogra, and  L. S. Van Winkle, M. V. Fanucchi, L. A. Miller et al., “Epithe- R. C. Welliver, “Macrophage inﬂammatory protein-1α (not T helper type 2 cytokines) is associated with severe forms of lial cell distribution and abundance in rhesus monkey airways during postnatal lung growth and development,” respiratory syncytial virus bronchiolitis,” Journal of Infectious Diseases, vol. 184, no. 4, pp. 393–399, 2001. Journal of Applied Physiology, vol. 97, no. 6, pp. 2355–2363,  L. Bont, C. J. Heijnen, A. Kavelaars et al., “Local interferon- γ levels during respiratory syncytial virus lower respiratory  C. H. GeurtsvanKessel and B. N. Lambrecht, “Division of tract infection are associated with disease severity,” Journal of labor between dendritic cell subsets of the lung,” Mucosal Immunology, vol. 1, no. 6, pp. 442–450, 2008. Infectious Diseases, vol. 184, no. 3, pp. 355–358, 2001.  J. P. Legg, I. R. Hussain, J. A. Warner, S. L. Johnston, and J.  K. Flurkey, J. M. Currer, and D. E. Harrison, “Mouse models O. Warner, “Type 1 and type 2 cytokine imbalance in acute in aging research,” in The Mouse in Biomedical Research,J. respiratory syncytial virus bronchiolitis,” American Journal of G. Fox, M. T. Davisson, F. W. Quimby, S. W. Barthold, C. Respiratory and Critical Care Medicine, vol. 168, no. 6, pp. E. Newcomer, and A. L. Smith, Eds., p. 63772, American 633–639, 2003. College Laboratory Animal Medicine, Elsevier, Burlington, Mass, USA, 2007.  M. A. Gill, A. K. Palucka, T. Barton et al., “Mobilization of  C. G. Plopper and D. M. Hyde, “The non-human primate plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral as a model for studying COPD and asthma,” Pulmonary Journal of Allergy 9 Pharmacology and Therapeutics, vol. 21, no. 5, pp. 755–766,  J. W. Hampton and C. Matthews, “Similarities between bab- 2008. oon and human blood clotting,” Journal of Applied Physiol- ogy, vol. 21, no. 6, pp. 1713–1716, 1966.  J. Gordon,G.Grafton,P.M.Wood,M.Larche, ´ and R. J.  I. Gomes, T. T. Sharma, N. Mahmud et al., “Highly abundant Armitage, “Modelling the human immune response: can genes in the transcriptosome of human and baboon CD34 mice be trusted?” Current Opinion in Pharmacology, vol. 1, no. 4, pp. 431–435, 2001. antigen-positive bone marrow cells,” Blood,vol. 98, no.1,pp. 93–99, 2001.  J. Mestas and C. C. W. Hughes, “Of mice and not men: dif-  A. Denjean, B. Arnoux, and R. Masse, “Acute eﬀects of ferences between mouse and human immunology,” Journal of intratracheal administration of platelet-activating factor in Immunology, vol. 172, no. 5, pp. 2731–2738, 2004. baboons,” Journal of Applied Physiology, vol. 55, no. 3, pp.  M. Rehli, “Of mice and men: species variations of Toll-like 799–804, 1983. receptor expression,” Trends in Immunology, vol. 23, no. 8,  S. Awasthi, J. J. Coalson, E. Crouch, F. Yang, and R. J. pp. 375–378, 2002. King, “Surfactant proteins A and D in premature baboons  M. Collin, V. Bigley, M. Haniﬀa, and S. Hambleton, “Human with chronic lung injury (bronchopulmonary dysplasia): dendritic cell deﬁciency: the missing ID?” Nature Reviews evidence for an inhibition of secretion,” American Journal of Immunology, vol. 11, no. 9, pp. 575–583, 2011. Respiratory and Critical Care Medicine, vol. 160, no. 3, pp.  F. Geissmann, “The origin of dendritic cells,” Nature 942–949, 1999. Immunology, vol. 8, no. 6, pp. 558–560, 2007.  S. Awasthi, J. J. Coalson, B. A. Yoder, E. Crouch, and R. J.  K. Shortman and S. H. Naik, “Steady-state and inﬂammatory King, “Deﬁciencies in lung surfactant proteins A and D are dendritic-cell development,” Nature Reviews Immunology, associated with lung infection in very premature neonatal vol. 7, no. 1, pp. 19–30, 2007. baboons,” American Journal of Respiratory and Critical Care  M. V. Avdalovic, L. F. Putney, E. S. Schelegle et al., “Vascular Medicine, vol. 163, no. 2, pp. 389–397, 2001. remodeling is airway generation-speciﬁc in a primate model  S. Awasthi, J. Cropper, and K. M. Brown, “Developmental of chronic asthma,” American Journal of Respiratory and expression of Toll-like receptors-2 and -4 in preterm baboon Critical Care Medicine, vol. 174, no. 10, pp. 1069–1076, 2006. lung,” Developmental and Comparative Immunology, vol. 32,  E. S. Schelegle, L. J. Gershwin, L. A. Miller et al., “Allergic no. 9, pp. 1088–1098, 2008. asthma induced in rhesus monkeys by house dust mite  D. N. Kotton, “Next-generation regeneration: the hope (Dermatophagoides farinae),” American Journal of Pathology, and hype of lung stem cell research,” American Journal of vol. 158, no. 1, pp. 333–341, 2001. Respiratory and Critical Care Medicine, vol. 185, no. 12, pp.  N. E. Schlabritz-Loutsevitch, G. B. Hubbard, M. J. Dammann 1255–1260, 2012. et al., “Normal concentrations of essential and toxic elements  K. Bratke, M. Lommatzsch, P. Julius et al., “Dendritic cell in pregnant baboons and fetuses (Papio species),” Journal of subsets in human bronchoalveolar lavage ﬂuid after segmen- Medical Primatology, vol. 33, no. 3, pp. 152–162, 2004. tal allergen challenge,” Thorax, vol. 62, no. 2, pp. 168–175,  B. F. Barrier, E. J. Dick, S. D. Butler, and G. B. Hub- bard, “Endometriosis involving the ileocaecal junction with  J. Kayserova, I. Zentsova-Jaresova, V. Budinsky et al., regional lymph node involvement in the baboon—striking “Selective increase in blood dendritic cell antigen-3-positive pathological ﬁnding identical between the human and the dendritic cells in bronchoalveolar lavage ﬂuid in allergic baboon: a case report,” Human Reproduction, vol. 22, no. 1, patients,” Scandinavian Journal of Immunology, vol. 75, no. pp. 272–274, 2007. 3, pp. 305–313, 2012.  L. D. Giavedoni, N. Schlabritz-Loutsevitch, V. L. Hodara et  I. M. J. Beeren, M. S. De Bruin-Weller, C. Ra, I. Kok, C. A. F. al., “Phenotypic changes associated with advancing gestation M. Bruinzeel-Koomen, and E. F. Knol, “Expression of FcεRI in maternal and fetal baboon lymphocytes,” Journal of on dendritic cell subsets in peripheral blood of patients with Reproductive Immunology, vol. 64, no. 1-2, pp. 121–132, 2004. atopic dermatitis and allergic asthma,” Journal of Allergy and  N. E. Schlabritz-Loutsevitch, G. B. Hubbard, P. A. Frost et Clinical Immunology, vol. 116, no. 1, pp. 228–229, 2005. al., “Abdominal pregnancy in a baboon: a ﬁrst case report,”  J. M. Tunon-De-Lara, A. E. Redington, P. Bradding et al., Journal of Medical Primatology, vol. 33, no. 1, pp. 55–59, 2004. “Dendritic cells in normal and asthmatic airways: expression  N. Goncharov, G. Katzija, and T. Todua, “Peripheral plasma of the a subunit of the high aﬃnity immunoglobulin E levels of 12 steroids during pregnancy in the baboon (Papio receptor (FcεRI-α),” Clinical and Experimental Allergy, vol. hamadryas),” European Journal of Obstetrics Gynecology and 26, no. 6, pp. 648–655, 1996. Reproductive Biology, vol. 11, no. 3, pp. 201–208, 1980.  M. Spears, C. Mcsharry, I. Donnelly et al., “Peripheral blood  N. Goncharov, T. Aso, and Z. Cekan, “Hormonal changes dendritic cell subtypes are signiﬁcantly elevated in subjects during the menstrual cycle of the baboon (Papio hamadr- with asthma,” Clinical and Experimental Allergy, vol. 41, no. yas),” Acta Endocrinologica, vol. 82, no. 2, pp. 396–412, 1976. 5, pp. 665–672, 2011.  L. R. Sibal and K. J. Samson, “Nonhuman primates: a critical  B. Dua, R. M. Watson, G. M. Gauvreau, and P. M. O’Byrne, role in current disease research,” ILAR Journal,vol. 42, no.2, “Myeloid and plasmacytoid dendritic cells in induced spu- pp. 74–84, 2001. tum after allergen inhalation in subjects with asthma,”  J. J. Coalson, V. T. Winter, T. Siler-Khodr, and B. A. Yoder, Journal of Allergy and Clinical Immunology, vol. 126, no. 1, “Neonatal chronic lung disease in extremely immature bab- pp. 133–139, 2010. oons,” American Journal of Respiratory and Critical Care  B. Foster, D. D. Metcalfe, and C. Prussin, “Human dendritic Medicine, vol. 160, no. 4, pp. 1333–1346, 1999. cell 1 and dendritic cell 2 subsets express FcεRI: correlation  M. H. Shearer, R. D. Dark, J. Chodosh, and R. C. Kennedy, with serum IgE and allergic asthma,” Journal of Allergy and “Comparison and characterization of immunoglobulin G Clinical Immunology, vol. 112, no. 6, pp. 1132–1138, 2003. subclasses among primate species,” Clinical and Diagnostic  M. M. Hagendorens, D. G. Ebot, A. J. Schuerwegh et al., Laboratory Immunology, vol. 6, no. 6, pp. 953–958, 1999. “Diﬀerences in circulating dendritic cell subtypes in cord 10 Journal of Allergy blood and peripheral blood of healthy and allergic children,” Clinical and Experimental Allergy, vol. 33, no. 5, pp. 633–639,  G. M. Mol ¨ ler, S. E. Overbeek, C. G. Van Helden-Meeuwsen et al., “Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids,” Clinical and Experimental Allergy, vol. 26, no. 5, pp. 517–524, 1996.  F. L. Jahnsen, F. Lund-Johansen, J. F. Dunne, L. Farkas, R. Haye, and P. Brandtzaeg, “Experimentally induced recruit- ment of plasmacytoid (CD123high) dendritic cells in human nasal allergy,” Journal of Immunology, vol. 165, no. 7, pp. 4062–4068, 2000.  H. Matsuda, T. Suda, H. Hashizume et al., “Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 8, pp. 1050–1054, 2002.  J. W. Upham, G. Zhang, A. Rate et al., “Plasmacytoid den- dritic cells during infancy are inversely associated with child- hood respiratory tract infections and wheezing,” Journal of Allergy and Clinical Immunology, vol. 124, no. 4, pp. 707– 713.e2, 2009.  A. Faith, N. Singh, E. Chevretton et al., “Counter regulation of the high aﬃnity IgE receptor, FcηRI, on human airway dendritic cells by IL-4 and IL-10,” Allergy, vol. 64, no. 11, pp. 1602–1607, 2009. 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