Advertisement

Innate Immune Responses and Bronchiolitis Obliterans Syndrome

  • Jamie L. ToddEmail author
  • Scott M. Palmer
Chapter
Part of the Respiratory Medicine book series (RM, volume 8)

Abstract

The innate immune system, central to host defense, is now recognized to play a critical role in regulating adaptive immune responses, including allograft rejection. Innate immunity is of particular importance in lung transplantation, given the specialized innate defense mechanisms within the lung and the constant interaction between the allograft and the external environment. A central principle of innate immunity is the recognition of highly conserved molecular patterns present on microbial pathogens or injured tissue by host innate pattern recognition receptors (PRRs). The Toll-like receptors (TLRs) are the best described and most extensively studied PRRs of relevance to transplant rejection. For example, in animal models, genetic inhibition of TLR signaling attenuates allograft rejection, while TLR activation impedes successful transplant tolerance. These findings have been translated into clinical lung transplantation, as we have shown that functional polymorphisms in the innate receptors TLR4 and CD14 impact the risk for acute rejection and bronchiolitis obliterans syndrome (BOS). Consequently, a more complex view of BOS pathogenesis that considers the influence of previously identified clinical risk factors on activation of both innate and adaptive immunity has emerged. While additional studies are needed to define the full spectrum of innate ligands and PRRs relevant to lung transplantation, it is clear that innate mechanisms are likely to play a central role in mediating lung allograft rejection and BOS. Selective inhibition of innate pathways represents an attractive approach that could complement existing immunosuppressive strategies to reduce rejection after lung transplantation.

Keywords

Bronchiolitis obliterans Allograft tolerance Innate immunity Toll-like receptor Pattern recognition receptor 

References

  1. 1.
    Medzhitov R, Janeway Jr C. Innate immunity. N Engl J Med. 2000;343(5):338–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Trinchieri G, Kubin M, Bellone G, Cassatella MA. Cytokine cross-talk between phagocytic cells and lymphocytes: relevance for differentiation/activation of phagocytic cells and regulation of adaptive immunity. J Cell Biochem. 1993;53(4):301–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhang P, Summer WR, Bagby GJ, Nelson S. Innate immunity and pulmonary host defense. Immunol Rev. 2000;173(1):39–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Zaas AK, Schwartz DA. Innate immunity and the lung: defense at the interface between host and environment. Trends Cardiovasc Med. 2005;15(6):195–202.PubMedCrossRefGoogle Scholar
  5. 5.
    Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5(1):58–68. doi: 10.1038/nri1528.PubMedCrossRefGoogle Scholar
  6. 6.
    Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003;3(9):710–20. doi: 10.1038/nri1180.PubMedCrossRefGoogle Scholar
  7. 7.
    Dunkelberger JR, Song W-C. Complement and its role in innate and adaptive immune responses. Cell Res. 2009;20(1):34–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Martin TR, Frevert CW. Innate immunity in the lungs. Proc Am Thorac Soc. 2005;2(5):403–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Gelman AE, Li W, Richardson SB, Zinselmeyer BH, Lai J, Okazaki M, et al. Cutting edge: acute lung allograft rejection is independent of secondary lymphoid organs. J Immunol. 2009;182(7):3969–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7(3):179–90.PubMedCrossRefGoogle Scholar
  11. 11.
    Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Medzhitov R, Janeway Jr C. The Toll receptor family and microbial recognition. Trends Microbiol. 2000;8(10):452–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Imler JL, Hoffmann JA. Toll receptors in innate immunity. Trends Cell Biol. 2001;11(7):304–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511. doi: 10.1038/nri1391.PubMedCrossRefGoogle Scholar
  17. 17.
    OPTN/SRT 2010 Annual Report. [7 Apr 2012]; http://www.srtr.org/annual_reports.
  18. 18.
    Ahmed EB, Daniels M, Alegre ML, Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev (Orlando). 2011;25(1):27–35.CrossRefGoogle Scholar
  19. 19.
    Palmer SM, Burch LH, Trindade AJ, Davis RD, Herczyk WF, Reinsmoen NL, et al. Innate immunity influences long-term outcomes after human lung transplant. Am J Respir Crit Care Med. 2005;171(7):780–5.PubMedCrossRefGoogle Scholar
  20. 20.
    He H, Stone JR, Perkins DL. Analysis of robust innate immune response after transplantation in the absence of adaptive immunity. Transplantation. 2002;73(6):853–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Christopher K, Mueller TF, Ma C, Liang Y, Perkins DL. Analysis of the innate and adaptive phases of allograft rejection by cluster analysis of transcriptional profiles. J Immunol. 2002;169(1):522–30.PubMedGoogle Scholar
  22. 22.
    Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest. 2003;111(10):1571–8.PubMedGoogle Scholar
  23. 23.
    Tesar BM, Zhang J, Li Q, Goldstein DR. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88, a Toll-like receptor signal adaptor protein. Am J Transplant. 2004;4(9):1429–39.PubMedCrossRefGoogle Scholar
  24. 24.
    McKay D, Shigeoka A, Rubinstein M, Surh C, Sprent J. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection. Eur J Immunol. 2006;36(8):1994–2002.PubMedCrossRefGoogle Scholar
  25. 25.
    Thornley TB, Brehm MA, Markees TG, Shultz LD, Mordes JP, Welsh RM, et al. TLR agonists abrogate costimulation blockade-induced prolongation of skin allografts. J Immunol. 2006;176(3):1561–70.PubMedGoogle Scholar
  26. 26.
    Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, et al. TLR engagement prevents transplantation tolerance. Am J Transplant. 2006;6(10):2282–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Garantziotis S, Palmer SM, Snyder LD, Ganous T, Chen BJ, Wang T, et al. Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide. Transplantation. 2007;84(8):1012–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kinnier CV, Martinu T, Gowdy KM, Nugent JL, Kelly FL, Palmer SM. Innate immune activation by the viral PAMP poly I:C potentiates pulmonary graft-versus-host disease after allogeneic hematopoietic cell transplant. Transpl Immunol. 2011;24(2):83–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Porrett PM, Yuan X, LaRosa DF, Walsh PT, Yang J, Gao W, et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands. J Immunol. 2008;181(3):1692–9.PubMedGoogle Scholar
  30. 30.
    Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am J Transplant. 2011;11(5):936–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen L, Ahmed E, Wang T, Wang Y, Ochando J, Chong AS, et al. TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol. 2009;182(10):6217–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25(2):187–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Goldstein DR, Palmer SM. Role of Toll-like receptor-driven innate immunity in thoracic organ transplantation. J Heart Lung Transplant. 2005;24(11):1721–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Palmer SM, Burch LH, Davis RD, Herczyk WF, Howell DN, Reinsmoen NL, et al. The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med. 2003;168(6):628–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Palmer SM, Klimecki W, Yu L, Reinsmoen NL, Snyder LD, Ganous TM, et al. Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14. Am J Transplant. 2007;7(3):693–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Kwan WH, van der Touw W, Heeger PS. Complement regulation of T cell immunity. Immunol Res. 2012;54(1–3):247–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med. 2002;8(6):582–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Pavlov V, Raedler H, Yuan S, Leisman S, Kwan WH, Lalli PN, et al. Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection. J Immunol. 2008;181(7):4580–9.PubMedGoogle Scholar
  39. 39.
    Gueler F, Rong S, Gwinner W, Mengel M, Brocker V, Schon S, et al. Complement 5a receptor inhibition improves renal allograft survival. J Am Soc Nephrol. 2008;19(12):2302–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Vieyra M, Leisman S, Raedler H, Kwan WH, Yang M, Strainic MG, et al. Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection. Am J Pathol. 2011;179(2):766–74.PubMedCrossRefGoogle Scholar
  41. 41.
    Raedler H, Vieyra MB, Leisman S, Lakhani P, Kwan W, Yang M, et al. Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice. Am J Transplant. 2011;11(7):1397–406.PubMedCrossRefGoogle Scholar
  42. 42.
    Khan MA, Jiang X, Dhillon G, Beilke J, Holers VM, Atkinson C, et al. CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants. Circ Res. 2011;109(11):1290–301.PubMedCrossRefGoogle Scholar
  43. 43.
    Murata K, Iwata T, Nakashima S, Fox-Talbot K, Qian Z, Wilkes DS, et al. C4d deposition and cellular infiltrates as markers of acute rejection in rat models of orthotopic lung transplantation. Transplantation. 2008;86(1):123–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Brown KM, Kondeatis E, Vaughan RW, Kon SP, Farmer CK, Taylor JD, et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med. 2006;354(19):2014–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Hodge S, Dean M, Hodge G, Holmes M, Reynolds PN. Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2011;30(5):589–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Carroll KE, Dean MM, Heatley SL, Meehan AC, Mifsud NA, Kotsimbos TC, et al. High levels of mannose-binding lectin are associated with poor outcomes after lung transplantation. Transplantation. 2011;91(9):1044–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Munster JM, van der Bij W, Breukink MB, van der Steege G, Zuurman MW, Hepkema BG, et al. Association between donor MBL promoter haplotype and graft survival and the development of BOS after lung transplantation. Transplantation. 2008;86(12):1857–63.PubMedCrossRefGoogle Scholar
  48. 48.
    Meloni F, Salvini R, Bardoni AM, Passadore I, Solari N, Vitulo P, et al. Bronchoalveolar lavage fluid proteome in bronchiolitis obliterans syndrome: possible role for surfactant protein A in disease onset. J Heart Lung Transplant. 2007;26(11):1135–43.PubMedCrossRefGoogle Scholar
  49. 49.
    Anderson RL, Hiemstra PS, Ward C, Forrest IA, Murphy D, Proud D, et al. Antimicrobial peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Eur Respir J. 2008;32(3):670–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Nelsestuen GL, Martinez MB, Hertz MI, Savik K, Wendt CH. Proteomic identification of human neutrophil alpha-defensins in chronic lung allograft rejection. Proteomics. 2005;5(6):1705–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Ross DJ, Cole AM, Yoshioka D, Park AK, Belperio JA, Laks H, et al. Increased bronchoalveolar lavage human beta-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2004;78(8):1222–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Han W, Wang W, Mohammed KA, Su Y. α-Defensins increase lung fibroblast proliferation and collagen synthesis via the β-catenin signaling pathway. FEBS J. 2009;276(22):6603–14.PubMedCrossRefGoogle Scholar
  53. 53.
    Lechler R, Ng WF, Steinman RM. Dendritic cells in transplantation—friend or foe? Immunity. 2001;14(4):357–68.PubMedCrossRefGoogle Scholar
  54. 54.
    Murphy SP, Porrett PM, Turka LA. Innate immunity in transplant tolerance and rejection. Immunol Rev. 2011;241(1):39–48.PubMedCrossRefGoogle Scholar
  55. 55.
    Lechler RI, Batchelor JR. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med. 1982;155(1):31–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Benson HL, Suzuki H, Lott J, Fisher AJ, Walline C, Heidler KM, et al. Donor lung derived myeloid and plasmacytoid dendritic cells differentially regulate T cell proliferation and cytokine production. Respir Res. 2012;13:25.PubMedCrossRefGoogle Scholar
  57. 57.
    Oyaizu T, Okada Y, Shoji W, Matsumura Y, Shimada K, Sado T, et al. Reduction of recipient macrophages by gadolinium chloride prevents development of obliterative airway disease in a rat model of heterotopic tracheal transplantation. Transplantation. 2003;76(8):1214–20.PubMedCrossRefGoogle Scholar
  58. 58.
    Kitchens WH, Chase CM, Uehara S, Cornell LD, Colvin RB, Russell PS, et al. Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant. 2007;7(12):2675–82.PubMedCrossRefGoogle Scholar
  59. 59.
    Paantjens AW, van de Graaf EA, Heerkens HD, Kwakkel-van Erp JM, Hoefnagel T, van Kessel DA, et al. Chimerism of dendritic cell subsets in peripheral blood after lung transplantation. J Heart Lung Transplant. 2011;30(6):691–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Rizzo M, SivaSai KS, Smith MA, Trulock EP, Lynch JP, Patterson GA, et al. Increased expression of inflammatory cytokines and adhesion molecules by alveolar macrophages of human lung allograft recipients with acute rejection: decline with resolution of rejection. J Heart Lung Transplant. 2000;19(9):858–65.PubMedCrossRefGoogle Scholar
  61. 61.
    Kreisel D, Sugimoto S, Tietjens J, Zhu J, Yamamoto S, Krupnick AS, et al. Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. J Clin Invest. 2011;121(1):265–76.PubMedCrossRefGoogle Scholar
  62. 62.
    Kreisel D, Sugimoto S, Zhu J, Nava R, Li W, Okazaki M, et al. Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance. Blood. 2011;118(23):6172–82.PubMedCrossRefGoogle Scholar
  63. 63.
    Belperio JA, Keane MP, Burdick MD, Gomperts B, Xue YY, Hong K, et al. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome. J Clin Invest. 2005;115(5):1150–62.PubMedGoogle Scholar
  64. 64.
    Slebos D-J, Postma DS, Koëter GH, van der Bij W, Boezen M, Kauffman HF. Bronchoalveolar lavage fluid characteristics in acute and chronic lung transplant rejection. J Heart Lung Transplant. 2004;23(5):532–40.PubMedCrossRefGoogle Scholar
  65. 65.
    Neurohr C, Huppmann P, Samweber B, Leuschner S, Zimmermann G, Leuchte H, et al. Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients. J Heart Lung Transplant. 2009;28(5):468–74.PubMedCrossRefGoogle Scholar
  66. 66.
    Reynaud-Gaubert M, Thomas P, Badier M, Cau P, Giudicelli R, Fuentes P. Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Am J Respir Crit Care Med. 2000;161(6):1924–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Maier S, Tertilt C, Chambron N, Gerauer K, Huser N, Heidecke C-D, et al. Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28−/− mice. Nat Med. 2001;7(5):557–62. doi: 10.1038/87880.PubMedCrossRefGoogle Scholar
  68. 68.
    Uehara S, Chase CM, Kitchens WH, Rose HS, Colvin RB, Russell PS, et al. NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts. J Immunol. 2005;175(5):3424–30.PubMedGoogle Scholar
  69. 69.
    Fildes JE, Yonan N, Tunstall K, Walker AH, Griffiths-Davies L, Bishop P, et al. Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation. J Heart Lung Transplant. 2008;27(2):203–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Snyder LD, Finlen-Copeland CA, Turbyfill WJ, Howell D, Willner DA, Palmer SM. Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation. Am J Respir Crit Care Med. 2010;181(12):1391–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Kumar D, Erdman D, Keshavjee S, Peret T, Tellier R, Hadjiliadis D, et al. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant. 2005;5(8):2031–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Weigt SS, Elashoff RM, Huang C, Ardehali A, Gregson AL, Kubak B, et al. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant. 2009;9(8):1903–11.PubMedCrossRefGoogle Scholar
  73. 73.
    Nawrot TS, Vos R, Jacobs L, Verleden SE, Wauters S, Mertens V, et al. The impact of traffic air pollution on bronchiolitis obliterans syndrome and mortality after lung transplantation. Thorax. 2011;66(9):748–54.PubMedCrossRefGoogle Scholar
  74. 74.
    Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc. 2009;6(1):39–46.PubMedCrossRefGoogle Scholar
  75. 75.
    Davis Jr RD, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, Steele MP, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125(3):533–42.PubMedCrossRefGoogle Scholar
  76. 76.
    Diamond JM, Lederer DJ, Kawut SM, Lee J, Ahya VN, Bellamy S, et al. Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis. Am J Transplant. 2011;11(11):2517–22.PubMedCrossRefGoogle Scholar
  77. 77.
    Pelaez A, Force SD, Gal AA, Neujahr DC, Ramirez AM, Naik PM, et al. Receptor for advanced glycation end products in donor lungs is associated with primary graft dysfunction after lung transplantation. Am J Transplant. 2010;10(4):900–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Christie JD, Shah CV, Kawut SM, Mangalmurti N, Lederer DJ, Sonett JR, et al. Plasma levels of receptor for advanced glycation end products, blood transfusion, and risk of primary graft dysfunction. Am J Respir Crit Care Med. 2009;180(10):1010–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Wu H, Ma J, Wang P, Corpuz TM, Panchapakesan U, Wyburn KR, et al. HMGB1 contributes to kidney ischemia reperfusion injury. J Am Soc Nephrol. 2010;21(11):1878–90.PubMedCrossRefGoogle Scholar
  80. 80.
    Wu H, Chen G, Wyburn KR, Yin J, Bertolino P, Eris JM, et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest. 2007;117(10):2847–59.PubMedCrossRefGoogle Scholar
  81. 81.
    Shigeoka AA, Holscher TD, King AJ, Hall FW, Kiosses WB, Tobias PS, et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J Immunol. 2007;178(10):6252–8.PubMedGoogle Scholar
  82. 82.
    Appel III JZ, Lee SM, Hartwig MG, Li B, Hsieh CC, Cantu III E, et al. Characterization of the innate immune response to chronic aspiration in a novel rodent model. Respir Res. 2007;8:87.PubMedCrossRefGoogle Scholar
  83. 83.
    Hartwig MG, Appel JZ, Li B, Hsieh CC, Yoon YH, Lin SS, et al. Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation. J Thorac Cardiovasc Surg. 2006;131(1):209–17.PubMedCrossRefGoogle Scholar
  84. 84.
    Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste JC, et al. Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax. 2010;65(8):690–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Li Z, Potts-Kant EN, Garantziotis S, Foster WM, Hollingsworth JW. Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS One. 2011;6(11):e27137.PubMedCrossRefGoogle Scholar
  86. 86.
    Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–14.PubMedCrossRefGoogle Scholar
  87. 87.
    Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant. 2002;21(5):559–66.PubMedCrossRefGoogle Scholar
  88. 88.
    Holt ND, Gould FK, Taylor CE, Harwood JF, Freeman R, Healy MD, et al. Incidence and significance of noncytomegalovirus viral respiratory infection after adult lung transplantation. J Heart Lung Transplant. 1997;16(4):416–9.PubMedGoogle Scholar
  89. 89.
    Palmer Jr SM, Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VF. Community respiratory viral infection in adult lung transplant recipients. Chest. 1998;113(4):944–50.PubMedCrossRefGoogle Scholar
  90. 90.
    Vilchez RA, Dauber J, Kusne S. Infectious etiology of bronchiolitis obliterans: the respiratory viruses connection—myth or reality? Am J Transplant. 2003;3(3):245–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Kuo E, Bharat A, Goers T, Chapman W, Yan L, Street T, et al. Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation. Ann Thorac Surg. 2006;82(3):1043–50.PubMedCrossRefGoogle Scholar
  92. 92.
    Bharat A, Kuo E, Saini D, Steward N, Hachem R, Trulock EP, et al. Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection. Ann Thorac Surg. 2010;90(5):1637–44; discussion 44.Google Scholar
  93. 93.
    Weigt SS, Elashoff RM, Keane MP, Strieter RM, Gomperts BN, Xue YY, et al. Altered levels of CC chemokines during pulmonary CMV predict BOS and mortality post-lung transplantation. Am J Transplant. 2008;8(7):1512–22.PubMedCrossRefGoogle Scholar
  94. 94.
    Garantziotis S, Palmer SM. An unwelcome guest: Aspergillus colonization in lung transplantation and its association with bronchiolitis obliterans syndrome. Am J Transplant. 2009;9(8):1705–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Kreisel D, Gelman AE, Palmer SM. In pursuit of new experimental models of obliterative bronchiolitis. Am J Transplant. 2011;11(5):882–3.PubMedCrossRefGoogle Scholar
  96. 96.
    Hennessy EJ, Parker AE, O’Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov. 2010;9(4):293–307.PubMedCrossRefGoogle Scholar
  97. 97.
    Axtelle T, Pribble J. An overview of clinical studies in healthy subjects and patients with severe sepsis with IC14, a CD14-specific chimeric monoclonal antibody. J Endotoxin Res. 2003;9(6):385–9.PubMedGoogle Scholar
  98. 98.
    Testa L, Van Gaal WJ, Bhindi R, Biondi-Zoccai GGL, Abbate A, Agostoni P, et al. Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients. J Thorac Cardiovasc Surg. 2008;136(4):884–93.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal MedicineDuke University Medical CenterDurhamUSA

Personalised recommendations