提示: 手机请竖屏浏览!

伊马替尼在重度难治性哮喘患者中的KIT抑制作用研究
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma


Katherine N. Cahill ... 呼吸系统疾病 • 2017.05.18
相关阅读
• 重度哮喘治疗的新靶点 • 成人重度和难治性哮喘 • tezepelumab治疗哮喘未得到控制的成人患者

摘要


背景

尽管经糖皮质激素治疗,重度哮喘患者的气道中仍可见肥大细胞;这些细胞与生活质量不佳和哮喘控制不良等疾病特点相关。干细胞因子及其受体KIT是肥大细胞稳态的核心。我们进行了一项原理论证试验,以评估KIT抑制剂伊马替尼在重度哮喘的生理学标志——气道高反应性,以及重度哮喘患者的气道肥大细胞数量和激活方面发挥的作用。

 

方法

我们在控制不良、接受最大剂量药物治疗后仍有气道高反应性的重度哮喘患者中进行了一项对伊马替尼的随机、双盲、安慰剂对照的24周试验。试验的主要终点是气道高反应性的改变。这一改变由降低第一秒用力呼气量20%所需乙酰甲胆碱的浓度(PC20)衡量。患者也经支气管镜检查。

 

结果

在62例经历随机分组的患者中,伊马替尼降低气道高反应性的程度比安慰剂大。第6个月时,与安慰剂组中乙酰甲胆碱PC20平均(±标准差)增加1.07±0.60标准剂量相比,伊马替尼组中增加1.73±0.60标准剂量(P=0.048)。血清类胰蛋白酶是肥大细胞激活的一个标志。与安慰剂组相比,伊马替尼也在较大程度上降低了血清类胰蛋白酶的水平(降低2.02±2.32 ng/mL对0.56±1.39 ng/mL,P=0.02)。两组中气道肥大细胞数量均减少。与安慰剂组相比,肌肉痉挛和低磷血症在伊马替尼组中更为常见。

 

结论

在重度哮喘患者中,伊马替尼降低了气道高反应性,减少了肥大细胞数量和类胰蛋白酶释放。这些结果表明,依赖KIT的过程和肥大细胞参与奠定了重度哮喘的病理生物学基础(由美国国立卫生研究院等资助;在ClinicalTrials.gov注册号为NCT01097694)。





作者信息

Katherine N. Cahill, M.D., Howard R. Katz, Ph.D., Jing Cui, M.D., Ph.D., Juying Lai, M.D., Shamsah Kazani, M.D., Allison Crosby-Thompson, M.S., Denise Garofalo, B.A., Mario Castro, M.D., Nizar Jarjour, M.D., Emily DiMango, M.D., Serpil Erzurum, M.D., Jennifer L. Trevor, M.D., Kartik Shenoy, M.D., Vernon M. Chinchilli, Ph.D., Michael E. Wechsler, M.D., Tanya M. Laidlaw, M.D., Joshua A. Boyce, M.D., and Elliot Israel, M.D.
From Brigham and Women’s Hospital, Harvard Medical School, Boston (K.N.C., H.R.K., J.C., J.L., A.C.-T., D.G., T.M.L., J.A.B., E.I.), and Novartis Institutes for BioMedical Research, Cambridge (S.K.) — both in Massachusetts; Washington University, St. Louis (M.C.); University of Wisconsin, Madison (N.J.); Columbia University Medical Center, New York (E.D.); Cleveland Clinic, Cleveland (S.E.); University of Alabama at Birmingham, Birmingham (J.L.T.); Temple University, Philadelphia (K.S.), and Pennsylvania State University, Hershey (V.M.C.) — both in Pennsylvania; and National Jewish Health, Denver (M.E.W.).Address reprint requests to Dr. Israel at the Divisions of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at eisrael@partners.org.

 

参考文献

1. Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med 2005;172:149-160

2. Chanez P, Wenzel SE, Anderson GP, et al. Severe asthma in adults: what are the important questions? J Allergy Clin Immunol 2007;119:1337-1348

3. Busse WW, Banks-Schlegel S, Wenzel SE. Pathophysiology of severe asthma. J Allergy Clin Immunol 2000;106:1033-1042

4. Limb SL, Brown KC, Wood RA, et al. Irreversible lung function deficits in young adults with a history of childhood asthma. J Allergy Clin Immunol 2005;116:1213-1219

5. Porsbjerg C, Rasmussen L, Nolte H, Backer V. Association of airway hyperresponsiveness with reduced quality of life in patients with moderate to severe asthma. Ann Allergy Asthma Immunol 2007;98:44-50

6. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159:1043-1051

7. Ward C, Johns DP, Bish R, et al. Reduced airway distensibility, fixed airflow limitation, and airway wall remodeling in asthma. Am J Respir Crit Care Med 2001;164:1718-1721

8. Bradding P, Walls AF, Holgate ST. The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol 2006;117:1277-1284

9. Siddiqui S, Mistry V, Doe C, et al. Airway hyperresponsiveness is dissociated from airway wall structural remodeling. J Allergy Clin Immunol 2008;122:335-341

10. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699-1705

11. Da Silva CA, Reber L, Frossard N. Stem cell factor expression, mast cells and inflammation in asthma. Fundam Clin Pharmacol 2006;20:21-39

12. Makowska JS, Cieslak M, Kowalski ML. Stem cell factor and its soluble receptor (c-kit) in serum of asthmatic patients- correlation with disease severity. BMC Pulm Med 2009;9:27-27

13. Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997;90:4947-4952

14. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925-932

15. Cerny-Reiterer S, Rabenhorst A, Stefanzl G, et al. Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia. Oncotarget 2015;6:3071-3084

16. Farha S, Dweik R, Rahaghi F, et al. Imatinib in pulmonary arterial hypertension: c-Kit inhibition. Pulm Circ 2014;4:452-455

17. Kraft M, Martin RJ, Lazarus SC, et al. Airway tissue mast cells in persistent asthma: predictor of treatment failure when patients discontinue inhaled corticosteroids. Chest 2003;124:42-50

18. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-907

19. Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol 1994;47:81-87

20. Prescribing information: Gleevec. Novartis, September 2016 (https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/gleevec_tabs.pdf).

21. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832-838

22. Revicki DA, Leidy NK, Brennan-Diemer F, Sorensen S, Togias A. Integrating patient preferences into health outcomes assessment: the multiattribute Asthma Symptom Utility Index. Chest 1998;114:998-1007

23. Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 1992;47:76-83

24. Morrow JD, Guzzo C, Lazarus G, Oates JA, Roberts LJ II. Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2. J Invest Dermatol 1995;104:937-940

25. Morrow JD, Minton TA. Improved assay for the quantification of 11-dehydrothromboxane B2 by gas chromatography-mass spectrometry. J Chromatogr 1993;612:179-185

26. Kim DC, Hsu FI, Barrett NA, et al. Cysteinyl leukotrienes regulate Th2 cell-dependent pulmonary inflammation. J Immunol 2006;176:4440-4448

27. Aysola RS, Hoffman EA, Gierada D, et al. Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology. Chest 2008;134:1183-1191

28. Gibson PG, Saltos N, Borgas T. Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma. J Allergy Clin Immunol 2000;105:752-759

29. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma — summary report 2007. J Allergy Clin Immunol 2007;120:Suppl:S94-138

30. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O’Byrne PM, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832-836

31. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014;371:1198-1207

32. Yu M, Eckart MR, Morgan AA, et al. Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J Clin Invest 2011;121:3133-3143

33. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001-1008

34. Boyd A, Ribeiro JM, Nutman TB. Human CD117 (cKit)+ innate lymphoid cells have a discrete transcriptional profile at homeostasis and are expanded during filarial infection. PLoS One 2014;9:e108649-e108649

35. Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol 2016;17:765-774

36. McKenzie AN, Spits H, Eberl G. Innate lymphoid cells in inflammation and immunity. Immunity 2014;41:366-374

37. Ingram JL, Bonner JC. EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases. Curr Mol Med 2006;6:409-421

服务条款 | 隐私政策 | 联系我们