Reply

Abstract

To the Editor:The correspondence from Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar provides important confirmation of and extends previous reports2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, 3Lisbonne M. Diem S. de Castro Keller A. Lefort J. Araujo L.M. Hachem P. et al.Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol. 2003; 171: 1637-1641PubMed Google Scholar, 4Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar, 5Pham-Thi N. de Blic J. Leite-de-Moraes M.C. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354 (author reply 2616): 2613-2616Crossref PubMed Scopus (68) Google Scholar regarding a role for invariant natural killer T (iNKT) cells in asthma. This report shows not only that iNKT cells are present in lung biopsies of patients with asthma but also that allergen challenge, which induced an increase in airway hyperreactivity (AHR), increased the number of iNKT cells in the lung of patients with asthma. These results are very consistent with previous studies in animal models of asthma (mice and monkeys), indicating that iNKT cells play a very important role in asthma, particularly in regulating the development of AHR.2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, 3Lisbonne M. Diem S. de Castro Keller A. Lefort J. Araujo L.M. Hachem P. et al.Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol. 2003; 171: 1637-1641PubMed Google Scholar, 6Matangkasombut P. Pichavant M. Yasumi T. Hendricks C. Savage P.B. Dekruyff R.H. et al.Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates.J Allergy Clin Immunol. 2008; 121: 1287-1289Abstract Full Text Full Text PDF PubMed Scopus (34) Google ScholarThis study is important because the very idea that iNKT cells are present in the lungs of patients with asthma has been controversial.4Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar Although a recent study of patients with a broad range of asthma severities appears to have resolved much of this issue by showing that many but not all patients with asthma indeed have increased numbers of lung iNKT cells, with pulmonary iNKT cells more consistently found in severe disease,8Matangkasombut P. Marigowda G. Ervine A. Idris L. Pichavant M. Kim H.Y. et al.Natural killer T cells in the lungs of patients with asthma.J Allergy Clin Immunol. 2009; 123: 1181-1185Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar goes beyond simply counting the number of iNKT cells in human lungs and begins to address the specific function of iNKT cells in human asthma. In mice, in which functional studies are more easily performed than in human beings, the development of AHR requires the presence of iNKT cells (elimination of iNKT cells abolishes AHR induced by allergen challenge2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, and direct activation of iNKT cells results in AHR9Meyer E.H. Goya S. Akbari O. Berry G.J. Savage P.B. Kronenberg M. et al.Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells.Proc Natl Acad Sci U S A. 2006; 103: 2782-2787Crossref PubMed Scopus (181) Google Scholar). Although the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar clearly does not directly show such relationships in human asthma, it does begin to address iNKT cell function in human asthma by showing that a dynamic increase in the number of lung iNKT cells is associated with an increase in AHR. As the first interventional study of human iNKT cells (using a specific clinical intervention, eg, allergen challenge), the report by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar suggests that pulmonary iNKT cells may function in human asthma by participating in the regulation of AHR after allergen challenge.In this study, the authors used α-Galactosylceramide (α-GalCer) loaded CD1d tetramers to stain lung tissue, a technique that definitively identifies iNKT cells. Although unloaded CD1d tetramer control staining was not used to help estimate the degree of nonspecific tetramer binding, the nonasthmatic control samples were negative for staining with the α-GalCer–loaded CD1d tetramer, and there was a significant increase in tetramer binding cells after allergen challenge. The sample size of the study was small, but this is the first study examining the number of iNKT cells in human lungs after allergen challenge, and therefore the study is commendable, and the results welcome.Thus, the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar adds incrementally to a growing body of evidence in human beings, monkeys, and mice supporting the hypothesis that iNKT cells play an important role in regulating the development of asthma. The story of iNKT cells in asthma, however, still has a long way to go, and we look forward to future experimentation in human beings that may provide further confirmation of this hypothesis—for example, by examining iNKT cells in viral exacerbations of asthma, examining AHR after direct activation of iNKT cells with glycolipids, or examining AHR after allergen challenge with and without blockade of iNKT cell activation. We believe that such studies will provide a more definitive assessment regarding a role of iNKT cells in human asthma. To the Editor: The correspondence from Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar provides important confirmation of and extends previous reports2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, 3Lisbonne M. Diem S. de Castro Keller A. Lefort J. Araujo L.M. Hachem P. et al.Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol. 2003; 171: 1637-1641PubMed Google Scholar, 4Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar, 5Pham-Thi N. de Blic J. Leite-de-Moraes M.C. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354 (author reply 2616): 2613-2616Crossref PubMed Scopus (68) Google Scholar regarding a role for invariant natural killer T (iNKT) cells in asthma. This report shows not only that iNKT cells are present in lung biopsies of patients with asthma but also that allergen challenge, which induced an increase in airway hyperreactivity (AHR), increased the number of iNKT cells in the lung of patients with asthma. These results are very consistent with previous studies in animal models of asthma (mice and monkeys), indicating that iNKT cells play a very important role in asthma, particularly in regulating the development of AHR.2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, 3Lisbonne M. Diem S. de Castro Keller A. Lefort J. Araujo L.M. Hachem P. et al.Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol. 2003; 171: 1637-1641PubMed Google Scholar, 6Matangkasombut P. Pichavant M. Yasumi T. Hendricks C. Savage P.B. Dekruyff R.H. et al.Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates.J Allergy Clin Immunol. 2008; 121: 1287-1289Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar This study is important because the very idea that iNKT cells are present in the lungs of patients with asthma has been controversial.4Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar Although a recent study of patients with a broad range of asthma severities appears to have resolved much of this issue by showing that many but not all patients with asthma indeed have increased numbers of lung iNKT cells, with pulmonary iNKT cells more consistently found in severe disease,8Matangkasombut P. Marigowda G. Ervine A. Idris L. Pichavant M. Kim H.Y. et al.Natural killer T cells in the lungs of patients with asthma.J Allergy Clin Immunol. 2009; 123: 1181-1185Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar goes beyond simply counting the number of iNKT cells in human lungs and begins to address the specific function of iNKT cells in human asthma. In mice, in which functional studies are more easily performed than in human beings, the development of AHR requires the presence of iNKT cells (elimination of iNKT cells abolishes AHR induced by allergen challenge2Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med. 2003; 9: 582-588Crossref PubMed Scopus (600) Google Scholar, and direct activation of iNKT cells results in AHR9Meyer E.H. Goya S. Akbari O. Berry G.J. Savage P.B. Kronenberg M. et al.Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells.Proc Natl Acad Sci U S A. 2006; 103: 2782-2787Crossref PubMed Scopus (181) Google Scholar). Although the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar clearly does not directly show such relationships in human asthma, it does begin to address iNKT cell function in human asthma by showing that a dynamic increase in the number of lung iNKT cells is associated with an increase in AHR. As the first interventional study of human iNKT cells (using a specific clinical intervention, eg, allergen challenge), the report by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar suggests that pulmonary iNKT cells may function in human asthma by participating in the regulation of AHR after allergen challenge. In this study, the authors used α-Galactosylceramide (α-GalCer) loaded CD1d tetramers to stain lung tissue, a technique that definitively identifies iNKT cells. Although unloaded CD1d tetramer control staining was not used to help estimate the degree of nonspecific tetramer binding, the nonasthmatic control samples were negative for staining with the α-GalCer–loaded CD1d tetramer, and there was a significant increase in tetramer binding cells after allergen challenge. The sample size of the study was small, but this is the first study examining the number of iNKT cells in human lungs after allergen challenge, and therefore the study is commendable, and the results welcome. Thus, the study by Reynolds et al1Reynolds C. Barkans J. Clark P. Kariyawasam H. Altmann D. Kay B. et al.Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma.J Allergy Clin Immunol. 2009; 124: 860-862Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar adds incrementally to a growing body of evidence in human beings, monkeys, and mice supporting the hypothesis that iNKT cells play an important role in regulating the development of asthma. The story of iNKT cells in asthma, however, still has a long way to go, and we look forward to future experimentation in human beings that may provide further confirmation of this hypothesis—for example, by examining iNKT cells in viral exacerbations of asthma, examining AHR after direct activation of iNKT cells with glycolipids, or examining AHR after allergen challenge with and without blockade of iNKT cell activation. We believe that such studies will provide a more definitive assessment regarding a role of iNKT cells in human asthma. Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthmaJournal of Allergy and Clinical ImmunologyVol. 124Issue 4PreviewTo the Editor: Full-Text PDF