Chronic Allograft Rejection: Epidemiology, Diagnosis, Pathogenesis, and Treatment

S. Samuel Weigt; W. Dean Wallace; Ariss Derhovanessian; Rajan Saggar; Rajeev Saggar; Joseph P Lynch; John A Belperio

doi:10.1055/s-0030-1249116

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2010; 31(2): 189-207
DOI: 10.1055/s-0030-1249116

Chronic Allograft Rejection: Epidemiology, Diagnosis, Pathogenesis, and Treatment

S. Samuel Weigt¹ , W. Dean Wallace² , Ariss Derhovanessian¹ , Rajan Saggar¹ , Rajeev Saggar¹ , Joseph P. Lynch¹ , John A. Belperio¹

¹Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
²Department of Pathology and Laboratory Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California

Abstract

ABSTRACT

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft rejection, in the form of obliterative bronchiolitis and its clinical correlate bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. The airway obstruction involved is classically progressive and unresponsive to treatment; however, the course is highly variable, and distinguishable phenotypes may exist. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome.

KEYWORDS

Lung transplantation - chronic rejection - bronchiolitis obliterans syndrome

Full Text

References

REFERENCES

1 Christie J D, Edwards L B, Aurora P et al.. The registry of the international society for heart and lung transplantation: twenty-sixth official adult lung and heart-lung transplantation Report-2009. J Heart Lung Transplant. 2009; 28 1031-1049
2 Stewart S, Fishbein M C, Snell G I et al.. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007; 26 1229-1242
3 Yousem S A, Berry G J, Cagle P T et al.. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996; 15(1 Pt 1) 1-15
4 Estenne M, Maurer J R, Boehler A et al.. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002; 21 297-310
5 Saggar R, Ross D J, Saggar R et al.. Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft. Am J Transplant. 2008; 8 1921-1930
6 Chalermskulrat W, Neuringer I P, Schmitz J L et al.. Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest. 2003; 123 1825-1831
7 Sundaresan S, Mohanakumar T, Smith M A et al.. HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome. Transplantation. 1998; 65 648-653
8 SivaSai K S, Smith M A, Poindexter N J et al.. Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Transplantation. 1999; 67 1094-1098
9 Stanford R E, Ahmed S, Hodson M, Banner N R, Rose M L. A role for indirect allorecognition in lung transplant recipients with obliterative bronchiolitis. Am J Transplant. 2003; 3 736-742
10 Duncan S R, Leonard C, Theodore J et al.. Oligoclonal CD4(+) T cell expansions in lung transplant recipients with obliterative bronchiolitis. Am J Respir Crit Care Med. 2002; 165 1439-1444
11 Bando K, Paradis I L, Similo S et al.. Obliterative bronchiolitis after lung and heart-lung transplantation: an analysis of risk factors and management. J Thorac Cardiovasc Surg. 1995; 110 4-13, discussion 13–14
12 Husain A N, Siddiqui M T, Holmes E W et al.. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 1999; 159 829-833
13 Scott A I, Sharples L D, Stewart S. Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies. Drugs. 2005; 65 761-771
14 Verleden G M, Dupont L J, Van Raemdonck D E. Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal?. Eur Respir J. 2005; 25 221-224
15 Le Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation. 2002; 73 1373-1381
16 Hopkins P M, Aboyoun C L, Chhajed P N et al.. Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis. Am J Respir Crit Care Med. 2004; 170 1022-1026
17 Burton C M, Iversen M, Scheike T, Carlsen J, Andersen C B. Minimal acute cellular rejection remains prevalent up to 2 years after lung transplantation: a retrospective analysis of 2697 transbronchial biopsies. Transplantation. 2008; 85 547-553
18 Kroshus T J, Kshettry V R, Savik K, John R, Hertz M I, Bolman III R M. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg. 1997; 114 195-202
19 Hachem R R, Khalifah A P, Chakinala M M et al.. The significance of a single episode of minimal acute rejection after lung transplantation. Transplantation. 2005; 80 1406-1413
20 Khalifah A P, Hachem R R, Chakinala M M et al.. Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome. Am J Transplant. 2005; 5 2022-2030
21 Hopkins P M, Aboyoun C L, Chhajed P N et al.. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant. 2002; 21 1062-1067
22 Baz M A, Layish D T, Govert J A et al.. Diagnostic yield of bronchoscopies after isolated lung transplantation. Chest. 1996; 110 84-88
23 Knoop C, Estenne M. Acute and chronic rejection after lung transplantation. Semin Respir Crit Care Med. 2006; 27 521-533
24 Tazelaar H D, Yousem S A. The pathology of combined heart-lung transplantation: an autopsy study. Hum Pathol. 1988; 19 1403-1416
25 Estenne M, Hertz M I. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med. 2002; 166 440-444
26 Girgis R E, Tu I, Berry G J et al.. Risk factors for the development of obliterative bronchiolitis after lung transplantation. J Heart Lung Transplant. 1996; 15 1200-1208
27 Sharples L D, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant. 2002; 21 271-281
28 Glanville A R, Aboyoun C L, Havryk A, Plit M, Rainer S, Malouf M A. Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation. Am J Respir Crit Care Med. 2008; 177 1033-1040
29 Burton C M, Iversen M, Scheike T, Carlsen J, Andersen C B. Is lymphocytic bronchiolitis a marker of acute rejection? An analysis of 2,697 transbronchial biopsies after lung transplantation. J Heart Lung Transplant. 2008; 27 1128-1134
30 Bittner H B, Dunitz J, Hertz M, Bolman III M R, Park S J. Hyperacute rejection in single lung transplantation—case report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation. 2001; 71 649-651
31 Choi J K, Kearns J, Palevsky H I et al.. Hyperacute rejection of a pulmonary allograft. Immediate clinical and pathologic findings. Am J Respir Crit Care Med. 1999; 160 1015-1018
32 de Jesus Peixoto Camargo J, Marcantonio Camargo S, Marcelo Schio S, Noguchi Machuca T, Adélia Perin F. Hyperacute rejection after single lung transplantation: a case report. Transplant Proc. 2008; 40 867-869
33 Frost A E, Jammal C T, Cagle P T. Hyperacute rejection following lung transplantation. Chest. 1996; 110 559-562
34 Scornik J C, Zander D S, Baz M A, Donnelly W H, Staples E D. Susceptibility of lung transplants to preformed donor-specific HLA antibodies as detected by flow cytometry. Transplantation. 1999; 68 1542-1546
35 Hadjiliadis D, Chaparro C, Reinsmoen N L et al.. Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study. J Heart Lung Transplant. 2005; 24(7, Suppl) S249-S254
36 Shah A S, Nwakanma L, Simpkins C, Williams J, Chang D C, Conte J V. Pretransplant panel reactive antibodies in human lung transplantation: an analysis of over 10,000 patients. Ann Thorac Surg. 2008; 85 1919-1924
37 Yousem S A, Martin T, Paradis I L, Keenan R, Griffith B P. Can immunohistological analysis of transbronchial biopsy specimens predict responder status in early acute rejection of lung allografts?. Hum Pathol. 1994; 25 525-529
38 Girnita A L, McCurry K R, Iacono A T et al.. HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection. J Heart Lung Transplant. 2004; 23 1135-1141
39 Girnita A L, Duquesnoy R, Yousem S A et al.. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant. 2005; 5 131-138
40 Palmer S M, Davis R D, Hadjiliadis D et al.. Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome. Transplantation. 2002; 74 799-804
41 Lau C L, Palmer S M, Posther K E et al.. Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients. Ann Thorac Surg. 2000; 69 1520-1524
42 Gammie J S, Pham S M, Colson Y L et al.. Influence of panel-reactive antibody on survival and rejection after lung transplantation. J Heart Lung Transplant. 1997; 16 408-415
43 Maruyama T, Jaramillo A, Narayanan K, Higuchi T, Mohanakumar T. Induction of obliterative airway disease by anti-HLA class I antibodies. Am J Transplant. 2005; 5 2126-2134
44 Takemoto S K, Zeevi A, Feng S et al.. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant. 2004; 4 1033-1041
45 Westall G P, Snell G I, McLean C, Kotsimbos T, Williams T, Magro C. C3d and C4d deposition early after lung transplantation. J Heart Lung Transplant. 2008; 27 722-728
46 Wallace W D, Reed E F, Ross D, Lassman C R, Fishbein M C. C4d staining of pulmonary allograft biopsies: an immunoperoxidase study. J Heart Lung Transplant. 2005; 24 1565-1570
47 Bharat A, Narayanan K, Street T et al.. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation. 2007; 83 150-158
48 Andrade C F, Waddell T K, Keshavjee S, Liu M. Innate immunity and organ transplantation: the potential role of toll-like receptors. Am J Transplant. 2005; 5 969-975
49 Palmer S M, Burch L H, Trindade A J et al.. Innate immunity influences long-term outcomes after human lung transplant. Am J Respir Crit Care Med. 2005; 171 780-785
50 Haque M A, Mizobuchi T, Yasufuku K et al.. Evidence for immune responses to a self-antigen in lung transplantation: role of type V collagen-specific T cells in the pathogenesis of lung allograft rejection. J Immunol. 2002; 169 1542-1549
51 Yoshida S, Haque A, Mizobuchi T et al.. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants. Am J Transplant. 2006; 6 724-735
52 Burlingham W J, Love R B, Jankowska-Gan E et al.. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007; 117 3498-3506
53 Goers T A, Ramachandran S, Aloush A, Trulock E, Patterson G A, Mohanakumar T. De novo production of K-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol. 2008; 180 4487-4494
54 Prekker M E, Nath D S, Walker A R et al.. Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J Heart Lung Transplant. 2006; 25 371-378
55 Christie J D, Kotloff R M, Ahya V N et al.. The effect of primary graft dysfunction on survival after lung transplantation. Am J Respir Crit Care Med. 2005; 171 1312-1316
56 Daud S A, Yusen R D, Meyers B F et al.. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2007; 175 507-513
57 D'Ovidio F, Mura M, Tsang M et al.. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005; 129 1144-1152
58 Young L R, Hadjiliadis D, Davis R D, Palmer S M. Lung transplantation exacerbates gastroesophageal reflux disease. Chest. 2003; 124 1689-1693
59 Blondeau K, Mertens V, Vanaudenaerde B A et al.. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008; 31 707-713
60 Cantu III E, Appel III J Z, Hartwig M G et al.. J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg. 2004; 78 1142-1151 discussion 1142-1151
61 Hartwig M G, Appel J Z, Davis R D. Antireflux surgery in the setting of lung transplantation: strategies for treating gastroesophageal reflux disease in a high-risk population. Thorac Surg Clin. 2005; 15 417-427
62 Davis Jr R D, Lau C L, Eubanks S et al.. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003; 125 533-542
63 Khalifah A P, Hachem R R, Chakinala M M et al.. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med. 2004; 170 181-187
64 Kumar D, Erdman D, Keshavjee S et al.. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant. 2005; 5 2031-2036
65 Neurohr C, Huppmann P, Leuchte H Munich Lung Transplant Group et al. Human herpesvirus 6 in bronchalveolar lavage fluid after lung transplantation: a risk factor for bronchiolitis obliterans syndrome?. Am J Transplant. 2005; 5 2982-2991
66 Heng D, Sharples L D, McNeil K, Stewart S, Wreghitt T, Wallwork J. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant. 1998; 17 1255-1263
67 Keenan R J, Lega M E, Dummer J S et al.. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation. 1991; 51 433-438
68 Keller C A, Cagle P T, Brown R W, Noon G, Frost A E. Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation. Chest. 1995; 107 973-980
69 Reichenspurner H, Girgis R E, Robbins R C et al.. Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1996; 62 1467-1472 discussion 1472-1473
70 Smith M A, Sundaresan S, Mohanakumar T et al.. Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg. 1998; 116 812-820
71 Weigt S S, Elashoff R M, Keane M P et al.. Altered levels of CC chemokines during pulmonary CMV predict BOS and mortality post-lung transplantation. Am J Transplant. 2008; 8 1512-1522
72 Luckraz H, Sharples L, McNeil K, Wreghitt T, Wallwork J. Cytomegalovirus antibody status of donor/recipient does not influence the incidence of bronchiolitis obliterans syndrome in lung transplantation. J Heart Lung Transplant. 2003; 22 287-291
73 Ruttmann E, Geltner C, Bucher B et al.. Combined CMV prophylaxis improves outcome and reduces the risk for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Transplantation. 2006; 81 1415-1420
74 Trulock E P, Christie J D, Edwards L B et al.. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report-2007. J Heart Lung Transplant. 2007; 26 782-795
75 Chmiel C, Speich R, Hofer M et al.. Ganciclovir/valganciclovir prophylaxis decreases cytomegalovirus-related events and bronchiolitis obliterans syndrome after lung transplantation. Clin Infect Dis. 2008; 46 831-839
76 Botha P, Archer L, Anderson R L et al.. Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome. Transplantation. 2008; 85 771-774
77 Vos R, Vanaudenaerde B M, Geudens N, Dupont L J, Van Raemdonck D E, Verleden G M. Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation?. Eur Respir J. 2008; 31 1037-1045
78 Weigt S S, Elashoff R M, Huang C et al.. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant. 2009; 9 1903-1911
79 Snyder L D, Palmer S M. Immune mechanisms of lung allograft rejection. Semin Respir Crit Care Med. 2006; 27 534-543
80 Belperio J A, Keane M P, Burdick M D et al.. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome. J Clin Invest. 2005; 115 1150-1162
81 Luckraz H, Goddard M, McNeil K, Atkinson C, Sharples L D, Wallwork J. Is obliterative bronchiolitis in lung transplantation associated with microvascular damage to small airways?. Ann Thorac Surg. 2006; 82 1212-1218
82 Babu A N, Murakawa T, Thurman J M et al.. Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis. J Clin Invest. 2007; 117 3774-3785
83 Verleden G, Dupont L. Obliterative bronchiolitis. In: Lynch JP III, Ross DJ Lung and Heart-Lung Transplantation. InformaUSA; 2006 217: 723-751
84 Hodge S, Holmes M, Banerjee B et al.. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am J Transplant. 2009; 9 727-733
85 Moudgil A, Bagga A, Toyoda M, Nicolaidou E, Jordan S C, Ross D. Expression of gamma-IFN mRNA in bronchoalveolar lavage fluid correlates with early acute allograft rejection in lung transplant recipients. Clin Transplant. 1999; 13 201-207
86 Iacono A, Dauber J, Keenan R et al.. Interleukin 6 and interferon-gamma gene expression in lung transplant recipients with refractory acute cellular rejection: implications for monitoring and inhibition by treatment with aerosolized cyclosporine. Transplantation. 1997; 64 263-269
87 Lu K C, Jaramillo A, Lecha R L et al.. Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2002; 74 1297-1302
88 Hodge G, Hodge S, Chambers D, Reynolds P N, Holmes M. Bronchiolitis obliterans syndrome is associated with absence of suppression of peripheral blood Th1 proinflammatory cytokines. Transplantation. 2009; 88 211-218
89 Neuringer I P, Walsh S P, Mannon R B, Gabriel S, Aris R M. Enhanced T cell cytokine gene expression in mouse airway obliterative bronchiolitis. Transplantation. 2000; 69 399-405
90 Räisänen-Sokolowski A, Glysing-Jensen T, Russell M E. Leukocyte-suppressing influences of interleukin (IL)-10 in cardiac allografts: insights from IL-10 knockout mice. Am J Pathol. 1998; 153 1491-1500
91 Meloni F, Vitulo P, Cascina A et al.. Bronchoalveolar lavage cytokine profile in a cohort of lung transplant recipients: a predictive role of interleukin-12 with respect to onset of bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2004; 23 1053-1060
92 Zhai Y, Ghobrial R M, Busuttil R W, Kupiec-Weglinski J W. Th1 and Th2 cytokines in organ transplantation: paradigm lost?. Crit Rev Immunol. 1999; 19 155-172
93 Keane M P, Gomperts B N, Weigt S et al.. IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome. J Immunol. 2007; 178 511-519
94 Lama V N, Harada H, Badri L N et al.. Obligatory role for interleukin-13 in obstructive lesion development in airway allografts. Am J Pathol. 2006; 169 47-60
95 Vanaudenaerde B M, De Vleeschauwer S I, Vos R et al.. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008; 8 1911-1920
96 Belperio J A, Burdick M D, Keane M P et al.. The role of the CC chemokine, RANTES, in acute lung allograft rejection. J Immunol. 2000; 165 461-472
97 Belperio J A, Keane M P, Burdick M D et al.. Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection. J Immunol. 2003; 171 4844-4852
98 Belperio J A, Keane M P, Burdick M D et al.. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest. 2001; 108 547-556
99 Belperio J A, Keane M P, Burdick M D et al.. Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome. J Immunol. 2002; 169 1037-1049
100 DiGiovine B, Lynch III J P, Martinez F J et al.. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol. 1996; 157 4194-4202
101 Reynaud-Gaubert M, Marin V, Thirion X et al.. Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration. J Heart Lung Transplant. 2002; 21 721-730
102 Vos R, Blondeau K, Vanaudenaerde B M et al.. Airway colonization and gastric aspiration after lung transplantation: do birds of a feather flock together?. J Heart Lung Transplant. 2008; 27 843-849
103 Neurohr C, Huppmann P, Samweber B Munich Lung Transplant Group et al. Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients. J Heart Lung Transplant. 2009; 28 468-474
104 Bröcker V, Länger F, Fellous T G et al.. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med. 2006; 173 1276-1282
105 Kleeberger W, Versmold A, Rothämel T et al.. Increased chimerism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury. Am J Pathol. 2003; 162 1487-1494
106 Lama V N, Smith L, Badri L et al.. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest. 2007; 117 989-996
107 Hertz M I, Henke C A, Nakhleh R E et al.. Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992; 89 10385-10389
108 Tikkanen J M, Hollmén M, Nykänen A I, Wood J, Koskinen P K, Lemström K B. Role of platelet-derived growth factor and vascular endothelial growth factor in obliterative airway disease. Am J Respir Crit Care Med. 2006; 174 1145-1152
109 Kallio E A, Koskinen P K, Aavik E, Buchdunger E, Lemström K B. Role of platelet-derived growth factor in obliterative bronchiolitis (chronic rejection) in the rat. Am J Respir Crit Care Med. 1999; 160 1324-1332
110 Aharinejad S, Taghavi S, Klepetko W, Abraham D. Prediction of lung-transplant rejection by hepatocyte growth factor. Lancet. 2004; 363 1503-1508
111 Charpin J M, Stern M, Grenet D, Israël-Biet D. Insulinlike growth factor-1 in lung transplants with obliterative bronchiolitis. Am J Respir Crit Care Med. 2000; 161 1991-1998
112 El-Gamel A, Sim E, Hasleton P et al.. Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation. J Heart Lung Transplant. 1999; 18 828-837
113 Burton C M, Carlsen J, Mortensen J, Andersen C B, Milman N, Iversen M. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2007; 26 681-686
114 Jackson C H, Sharples L D, McNeil K, Stewart S, Wallwork J. Acute and chronic onset of bronchiolitis obliterans syndrome (BOS): are they different entities?. J Heart Lung Transplant. 2002; 21 658-666
115 Lama V N, Murray S, Lonigro R J et al.. Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients. Am J Respir Crit Care Med. 2007; 175 1192-1198
116 Vermeulen K M, Groen H, van der Bij W, Erasmus M E, Koëter G H, TenVergert E M. The effect of bronchiolitis obliterans syndrome on health related quality of life. Clin Transplant. 2004; 18 377-383
117 van den Berg J W, van Enckevort P J, TenVergert E M, Postma D S, van der Bij W, Koëter G H. Bronchiolitis obliterans syndrome and additional costs of lung transplantation. Chest. 2000; 118 1648-1652
118 Vermuelen K M, van der Bij W, Erasmus M E, TenVergert E M. Long-term health-related quality of life after lung transplantation: different predictors for different dimensions. J Heart Lung Transplant. 2007; 26 188-193
119 Hachem R R, Chakinala M M, Yusen R D et al.. The predictive value of bronchiolitis obliterans syndrome stage 0-p. Am J Respir Crit Care Med. 2004; 169 468-472
120 Lama V N, Murray S, Mumford J A et al.. Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients. Am J Respir Crit Care Med. 2005; 172 379-383
121 Aboyoun C L, Tamm M, Chhajed P N et al.. Diagnostic value of follow-up transbronchial lung biopsy after lung rejection. Am J Respir Crit Care Med. 2001; 164 460-463
122 Chakinala M M, Ritter J, Gage B F et al.. Yield of surveillance bronchoscopy for acute rejection and lymphocytic bronchitis/bronchiolitis after lung transplantation. J Heart Lung Transplant. 2004; 23 1396-1404
123 Meloni F, Vitulo P, Bianco A M et al.. Regulatory CD4 + CD25 + T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation. 2004; 77 762-766
124 Fields R C, Bharat A, Steward N et al.. Elevated soluble CD30 correlates with development of bronchiolitis obliterans syndrome following lung transplantation. Transplantation. 2006; 82 1596-1601
125 Paantjens A W, Kwakkel-van Erp J M, van Ginkel W G et al.. Serum thymus and activation regulated chemokine levels post-lung transplantation as a predictor for the bronchiolitis obliterans syndrome. Clin Exp Immunol. 2008; 154 202-208
126 Mattsson J, Remberger M, Andersson O, Sundberg B, Nord M. Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation. 2005; 79 1411-1416
127 Glanville A R. The role of bronchoscopic surveillance monitoring in the care of lung transplant recipients. Semin Respir Crit Care Med. 2006; 27 480-491
128 Verleden G M, Vanaudenaerde B M, Dupont L J, Van Raemdonck D E. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006; 174 566-570
129 Zheng L, Walters E H, Ward C et al.. Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation. Thorax. 2000; 55 53-59
130 Crim C, Keller C A, Dunphy C H, Maluf H M, Ohar J A. Flow cytometric analysis of lung lymphocytes in lung transplant recipients. Am J Respir Crit Care Med. 1996; 153 1041-1046
131 Zeevi A, Rabinowich H, Paradis I et al.. Lymphocyte activation in bronchoalveolar lavages from heart-lung transplant recipients. Transplant Proc. 1988; 20 189-192
132 Gregson A L, Hoji A, Saggar R et al.. Bronchoalveolar immunologic profile of acute human lung transplant allograft rejection. Transplantation. 2008; 85 1056-1059
133 Whitehead B F, Stoehr C, Finkle C et al.. Analysis of bronchoalveolar lavage from human lung transplant recipients by flow cytometry. Respir Med. 1995; 89 27-34
134 Lande J D, Patil J, Li N, Berryman T R, King R A, Hertz M I. Novel insights into lung transplant rejection by microarray analysis. Proc Am Thorac Soc. 2007; 4 44-51
135 de Jong P A, Dodd J D, Coxson H O et al.. Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning. Thorax. 2006; 61 799-804
136 Bankier A A, Van Muylem A, Knoop C, Estenne M, Gevenois P A. Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology. 2001; 218 533-539
137 Estenne M, Van Muylem A, Knoop C, Antoine M. Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution. Am J Respir Crit Care Med. 2000; 162(3 Pt 1) 1047-1051
138 Reynaud-Gaubert M, Thomas P, Badier M, Cau P, Giudicelli R, Fuentes P. Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Functional and bronchoalveolar lavage cell findings. Am J Respir Crit Care Med. 2000; 161 1924-1929
139 Van Muylem A, Scillia P, Knoop C, Paiva M, Estenne M. Single-breath test in lateral decubitus reflects function of single lungs grafted for emphysema. J Appl Physiol. 2006; 100 834-838
140 Van Muylem A, Knoop C, Estenne M. Early detection of chronic pulmonary allograft dysfunction by exhaled biomarkers. Am J Respir Crit Care Med. 2007; 175 731-736
141 Dupont L J, Dewandeleer Y, Vanaudenaerde B M, Van Raemdonck D E, Verleden G M. The pH of exhaled breath condensate of patients with allograft rejection after lung transplantation. Am J Transplant. 2006; 6 1486-1492
142 Stanbrook M B, Kesten S. Bronchial hyperreactivity after lung transplantation predicts early bronchiolitis obliterans. Am J Respir Crit Care Med. 1999; 160 2034-2039
143 Allen D J, Fildes J E, Yonan N, Leonard C T. Changes in induced sputum in the presence of bronchiolitis obliterans syndrome and correlation with spirometry in single and bilateral lung transplant recipients. J Heart Lung Transplant. 2005; 24 88-91
144 Gast K K, Biedermann A, Herweling A et al.. Oxygen-sensitive 3He-MRI in bronchiolitis obliterans after lung transplantation. Eur Radiol. 2008; 18 530-537
145 Belperio J A, Weigt S S, Fishbein M C, Lynch III J P. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc. 2009; 6 108-121
146 Speich R, Boehler A, Thurnheer R, Weder W. Salvage therapy with mycophenolate mofetil for lung transplant bronchiolitis obliterans: importance of dosage. Transplantation. 1997; 64 533-535
147 Whyte R I, Rossi S J, Mulligan M S et al.. Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation. Ann Thorac Surg. 1997; 64 945-948
148 Borro J M, Bravo C, Solé A et al.. Conversion from cyclosporine to tacrolimus stabilizes the course of lung function in lung transplant recipients with bronchiolitis obliterans syndrome. Transplant Proc. 2007; 39 2416-2419
149 Cairn J, Yek T, Banner N R, Khaghani A, Hodson M E, Yacoub M. Time-related changes in pulmonary function after conversion to tacrolimus in bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2003; 22 50-57
150 Sarahrudi K, Carretta A, Wisser W et al.. The value of switching from cyclosporine to tacrolimus in the treatment of refractory acute rejection and obliterative bronchiolitis after lung transplantation. Transpl Int. 2002; 15 24-28
151 Snell G I, Esmore D S, Williams T J. Cytolytic therapy for the bronchiolitis obliterans syndrome complicating lung transplantation. Chest. 1996; 109 874-878
152 Kesten S, Rajagopalan N, Maurer J. Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation. Transplantation. 1996; 61 427-430
153 Martinu T, Howell D N, Davis R D, Steele M P, Palmer S M. Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients. Chest. 2006; 129 1016-1023
154 Reams B D, Musselwhite L W, Zaas D W et al.. Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant. 2007; 7 2802-2808
155 Gerhardt S G, McDyer J F, Girgis R E, Conte J V, Yang S C, Orens J B. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003; 168 121-125
156 Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008; 85 36-41
157 Porhownik N R, Batobara W, Kepron W, Unruh H W, Bshouty Z. Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients. Can Respir J. 2008; 15 199-202
158 Shitrit D, Bendayan D, Gidon S, Saute M, Bakal I, Kramer M R. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant. 2005; 24 1440-1443
159 Vanaudenaerde B M, Meyts I, Vos R et al.. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J. 2008; 32 832-843
160 Brugière O, Thabut G, Castier Y et al.. Lung retransplantation for bronchiolitis obliterans syndrome: long-term follow-up in a series of 15 recipients. Chest. 2003; 123 1832-1837
161 Kawut S M, Lederer D J, Keshavjee S et al.. Outcomes after lung retransplantation in the modern era. Am J Respir Crit Care Med. 2008; 177 114-120
162 Aigner C, Jaksch P, Taghavi S et al.. Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases. J Heart Lung Transplant. 2008; 27 60-65
163 Palmer S M, Miralles A P, Lawrence C M, Gaynor J W, Davis R D, Tapson V F. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest. 1999; 116 127-133
164 Hartwig M G, Snyder L D, Appel III J Z et al.. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant. 2008; 27 547-553
165 Ailawadi G, Smith P W, Oka T et al.. Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg. 2008; 135 594-602
166 Garrity Jr E R, Villanueva J, Bhorade S M, Husain A N, Vigneswaran W T. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody. Transplantation. 2001; 71 773-777
167 Lischke R, Simonek J, Davidová R et al.. Induction therapy in lung transplantation: initial single-center experience comparing daclizumab and antithymocyte globulin. Transplant Proc. 2007; 39 205-212
168 Brock M V, Borja M C, Ferber L et al.. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant. 2001; 20 1282-1290
169 McCurry K R, Iacono A, Zeevi A et al.. Early outcomes in human lung transplantation with thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg. 2005; 130 528-537
170 McNeil K, Glanville A R, Wahlers T et al.. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation. 2006; 81 998-1003
171 Keenan R J, Konishi H, Kawai A et al.. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg. 1995; 60 580-584, discussion 584–585
172 Treede H, Klepetko W, Reichenspurner H Munich and Vienna Lung Transplant Group et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant. 2001; 20 511-517
173 Hachem R R, Yusen R D, Chakinala M M et al.. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant. 2007; 26 1012-1018
174 Snell G I, Valentine V G, Vitulo P RAD B159 Study Group et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant. 2006; 6 169-177
175 Dutly A E, Gaspert A, Inci I, Schneiter D, Korom S, Weder W. The influence of the rapamycin-derivate SDZ RAD on the healing of airway anastomoses. Eur J Cardiothorac Surg. 2003; 24 154-158, discussion 158
176 Iacono A T, Johnson B A, Grgurich W F et al.. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006; 354 141-150
177 Appel III J Z, Hartwig M G, Davis R D, Reinsmoen N L. Utility of peritransplant and rescue intravenous immunoglobulin and extracorporeal immunoadsorption in lung transplant recipients sensitized to HLA antigens. Hum Immunol. 2005; 66 378-386
178 Astor T L, Galantowicz M, Phillips A, Palafox J, Baker P. Pulmonary capillaritis as a manifestation of acute humoral allograft rejection following infant lung transplantation. Am J Transplant. 2009; 9 409-412
179 Morrell M R, Patterson G A, Trulock E P, Hachem R R. Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant. 2009; 28 96-100
180 Perry D K, Burns J M, Pollinger H S et al.. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009; 9 201-209
181 Perry D K, Pollinger H S, Burns J M et al.. Two novel assays of alloantibody-secreting cells demonstrating resistance to desensitization with IVIG and rATG. Am J Transplant. 2008; 8 133-143
182 Ramos E J, Pollinger H S, Stegall M D, Gloor J M, Dogan A, Grande J P. The effect of desensitization protocols on human splenic B-cell populations in vivo. Am J Transplant. 2007; 7 402-407
183 Zand M S, Vo T, Huggins J et al.. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation. 2005; 79 1507-1515
184 Nimmerjahn F, Ravetch J V. The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med. 2007; 204 11-15
185 Neubert K, Meister S, Moser K et al.. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008; 14 748-755
186 Spencer H, Rampling D, Aurora P, Bonnet D, Hart S L, Jaffé A. Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation. Thorax. 2005; 60 60-62
187 Pham S M, Rao A S, Zeevi A et al.. Effects of donor bone marrow infusion in clinical lung transplantation. Ann Thorac Surg. 2000; 69 345-350

S. Samuel WeigtM.D.

The David Geffen School of Medicine at UCLA, Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology

10833 Le Conte Ave., 37-131 CHS, Los Angeles, CA 90095

Email: sweigt@mednet.ucla.edu