Page 605 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 583

NOVEL PATHWAYS TO THERAPY IN Recent clinical studies have confirmed the importance of
INFLAMMATORY AIRWAY DISEASE Th2- and ILC-derived cytokines, including IL-5 and IL-13, to
the pathogenesis of human allergic disease. The anti–IL-5 antibody
Intensive research conducted over the past several decades has mepolizumab was recently approved by the US Food and Drug
markedly improved our understanding of the immune and Administration (FDA) for use in eosinophilic asthma; anti–IL-13
environmental basis of allergic and nonallergic airway diseases. (lebrikizumab) and anti–IL-4/IL-13 receptor (dupilumab)
Currently available therapies for these diseases have, however, antibodies are likely to be approved for similar indications.
failed to match this level of sophistication. It is now clear that In addition to defining disease populations that are most
allergic disease is immunologically complex and likely to involve likely to benefit from them, a major challenge with all biological
multiple hypersensitivity mechanisms operating in parallel. Recent agents is their prohibitive cost. Development of small, relatively
studies also show that factors other than allergens likely critically easily manufactured molecules that antagonize disease-related
influence the airway immune response to inhaled antigens and pathways is, in many ways, a more attractive approach with lower
particulate matter. These adjuvant factors include cell wall pharmaceutical costs. Small molecule agonists of peroxisome
products of bacteria and fungi, such as lipopolysaccharide (LPS); proliferator activated receptor-γ (PPAR-γ) are currently approved
secreted factors, such as proteases; and endogenous factors from for use in diabetes mellitus (pioglitazone, rosiglitazone) in the
cells damaged by exposure to allergens and smoke. There is United States, but they are also outstanding antagonists of Th17
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increasing evidence that asthma and RS may be linked to respira- cells and can reverse experimental emphysema. Thus PPAR-γ
tory tract infections involving viruses, especially HRV, and fila- agonists are excellent candidates for future clinical trials in
mentous fungi. Future therapies are, therefore, likely to focus emphysema. Small molecule antagonists of IL-4/IL-13 signaling
on both endogenous factors that coordinate allergic inflammation that target STAT6 have also been discovered and are potentially
(e.g., cytokines) and etiological environmental factors (e.g., suitable for clinical trial and development. 45
proteases, fungi, and nCB). In future studies, it will be essential to clarify the role of
Once thought of as primarily a physical barrier, the respiratory chronic infections caused by viruses, bacteria, and fungi in asthma
epithelium is now recognized to actively coordinate immunity and RS. Although recent studies firmly implicate a central infec-
to allergens and other environmental challenges. Through release tious role for fungi in CRSwNP and asthma, it is a major challenge
of IL-33, IL-25 and/or TSLP, respiratory epithelial cells can initiate to design clinical trials that unequivocally demonstrate whether
and coordinate the innate and adaptive type 2 immune response antifungal antibiotics are useful in asthma and CRS. 9
(see Fig. 41.7). In addition, respiratory epithelial cells produce The central role played by proteases and the proteolytic
several chemokines in response to environmental triggers, activation of complement (e.g., C3) and coagulation-related
recruiting DCs, ILC2s, basophils, eosinophils, and mast cell inflammatory pathways (e.g., fibrinogen) in allergic diseases
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progenitors. Several of the triggers listed above and also trauma suggest that antiproteases might be effective in the management
to airway cells can activate the release of these type 2 cytokines of these conditions. Broad-spectrum antiproteases are effective
and chemokines. in attenuating human and experimental asthma and are, thus,
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The prototypical epithelial cell cytokines, IL-25, IL-33, and suitable for further therapeutic development. The major
TSLP, share many overlapping functions supporting a local type obstacles with these agents are discovering molecules with suf-
2 inflammatory response despite having unique receptors. As ficiently broad spectrum to inhibit the proteases of the many
expected, many of the type 2 cells, including eosinophils, DCs, fungi now linked to human allergic disease and overcoming
ILCs, and mast cells, express receptors to all three cytokines. potential safety issues related to their anticoagulant and immu-
Despite functional overlap, these cytokines also possess unique nosuppressive properties.
functions. For example, IL-33 and IL-25 activate different types
of ILCs, with IL-33 primarily activating ILC2 and IL-25 prefer- Please check your eBook at https://expertconsult.inkling.com/
entially stimulating a novel population of type 2 innate cells. for self-assessment questions. See inside cover for registration
TSLP is associated more with activation of the adaptive type 2 details.
inflammatory response via DCs. Also, TSLP uniquely supports
the hematopoiesis of basophils. Together, these epithelial cell
derived cytokines orchestrate a robust innate and adaptive type REFERENCES
2 inflammatory response as well as initiating necessary repairs
to the epithelial cell barrier. 43 1. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact
on Asthma (ARIA) 2008 update. Allergy 2008;63:8–160.
2. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis
ON THE HOrIZON and nasal polyps 2007. Rhinol Suppl 2007;20:1–136.
3. Calabria CW, Dietrich J, Hagan L. Comparison of serum-specific IgE
• Increasingly sophisticated clinical trials focused on interrupting key (ImmunoCAP) and skin-prick test results for 53 inhalant allergens in
immunological pathways (i.e., interleukin [IL]-4, IL-13 signaling pathway) patients with chronic rhinitis. Allergy Asthma Proc 2009;30:386–96.
in allergic disease 4. Hsueh WD, Conley DB, Kim H, et al. Identifying clinical symptoms for
• Focused research on the importance of infectious pathogens, microbial improving the symptomatic diagnosis of chronic rhinosinusitis. Int
adjuvant moieties, and air pollution in allergic disease initiation and Forum Allergy Rhinol 2013;3:307–14.
perpetuation
• Development of immunologically based diagnostic and prognostic 5. Bent JP 3rd, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol
strategies for asthma, chronic sinusitis, and possibly other allergic Head Neck Surg 1994;111:580–8.
airway disorders 6. Steinke JW, Wilson JM. Aspirin-exacerbated respiratory disease:
• Clinical studies that reassess the validity of the predominant use of pathophysiological insights and clinical advances. J Asthma Allergy
general immunosuppression in comparison to targeted antiinflammatory 2016;9:37–43.
approaches 7. Meltzer EO. The role of nasal corticosteroids in the treatment of rhinitis.
Immunol Allergy Clin North Am 2011;31:545–60.