PDF herunterladen
Semin Respir Crit Care Med 2006; 27(5): 534-543
DOI: 10.1055/s-2006-954610
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Immune Mechanisms of Lung Allograft Rejection

Laurie D. Snyder1 , Scott M. Palmer1
  • 1Department of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
26. Oktober 2006 (online)

    Lizenzen und Reprints

ABSTRACT

Extended survival after lung transplantation is primarily limited by progressive airflow obstruction and fibrotic obliteration of the small airways, termed bronchiolitis obliterans syndrome (BOS) and bronchiolitis obliterans (BO), respectively. BO is thought to represent the pulmonary-specific manifestation of chronic allograft rejection and the end result of a spectrum of different immunological insults to the allograft. Historically, research has focused on the adaptive immune system and its cellular-based rejection as the driving factor in the development of BO. Recent research in animal lung transplant models and human lung transplant recipients has identified that chemokines, humoral immunity, autoimmunity, and innate immunity also contribute to lung allograft rejection and BO. This review explores the complex immunological mechanisms that promote the high rate of pulmonary allograft failure and significantly impair survival after lung transplantation. We also identify areas for further research critical to improving transplant outcomes.

KEYWORDS

Lung transplant rejection - humoral immunity - autoimmunity - innate immunity

REFERENCES

  • 1 Trulock E P, Edwards L B, Taylor D O, Boucek M M, Keck B M, Hertz M I. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report-2005.  J Heart Lung Transplant. 2005;  24 956-967
    CrossrefPubMedGoogle Scholar
  • 2 Abernathy E C, Hruban R H, Baumgartner W A, Reitz B A, Hutchins G M. The two forms of bronchiolitis obliterans in heart-lung transplant recipients.  Hum Pathol. 1991;  22 1102-1110
    CrossrefPubMedGoogle Scholar
  • 3 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
    CrossrefPubMedGoogle Scholar
  • 4 Hertz M I, Jessurun J, King M B, Savik S K, Murray J J. Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways.  Am J Pathol. 1993;  142 1945-1951
    PubMedGoogle Scholar
  • 5 Brazelton T R, Adams B A, Cheung A C, Morris R E. Progression of obliterative airway disease occurs despite the removal of immune reactivity by retransplantation.  Transplant Proc. 1997;  29 2613
    CrossrefPubMedGoogle Scholar
  • 6 Chalermskulrat W, Neuringer I P, Brickey W J et al.. Hierarchical contributions of allorecognition pathways in chronic lung rejection.  Am J Respir Crit Care Med. 2003;  167 999-1007
    CrossrefPubMedGoogle Scholar
  • 7 Kelly K E, Hertz M I, Mueller D L. T-cell and major histocompatibility complex requirements for obliterative airway disease in heterotopically transplanted murine tracheas.  Transplantation. 1998;  66 764-771
    PubMedGoogle Scholar
  • 8 Higuchi T, Jaramillo A, Kaleem Z, Patterson G A, Mohanakumar T. Different kinetics of obliterative airway disease development in heterotopic murine tracheal allografts induced by CD4+ and CD8+ T cells.  Transplantation. 2002;  74 646-651
    PubMedGoogle Scholar
  • 9 Richards D M, Dalheimer S L, Ehst B D et al.. Indirect minor histocompatibility antigen presentation by allograft recipient cells in the draining lymph node leads to the activation and clonal expansion of CD4+ T cells that cause obliterative airways disease.  J Immunol. 2004;  172 3469-3479
    PubMedGoogle Scholar
  • 10 Richards D M, Dalheimer S L, Hertz M I, Mueller D L. Trachea allograft class I molecules directly activate and retain CD8+ T cells that cause obliterative airways disease.  J Immunol. 2003;  171 6919-6928
    PubMedGoogle Scholar
  • 11 Higuchi T, Maruyama T, Jaramillo A, Mohanakumar T. Induction of obliterative airway disease in murine tracheal allografts by CD8 + CTLs recognizing a single minor histocompatibility antigen.  J Immunol. 2005;  174 1871-1878
    PubMedGoogle Scholar
  • 12 Smith C R, Jaramillo A, Lu K C, Higuchi T, Kaleem Z, Mohanakumar T. Prevention of obliterative airway disease in HLA-A2-transgenic tracheal allografts by neutralization of tumor necrosis factor.  Transplantation. 2001;  72 1512-1518
    PubMedGoogle Scholar
  • 13 Boehler A, Bai X H, Liu M et al.. Upregulation of T-helper 1 cytokines and chemokine expression in post-transplant airway obliteration.  Am J Respir Crit Care Med. 1999;  159 1910-1917
    PubMedGoogle Scholar
  • 14 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
    CrossrefPubMedGoogle Scholar
  • 15 Koskinen P K, Kallio E A, Krebs R, Lemstrom K B. A dose-dependent inhibitory effect of cyclosporine A on obliterative bronchiolitis of rat tracheal allografts.  Am J Respir Crit Care Med. 1997;  155 303-312
    PubMedGoogle Scholar
  • 16 Adams B F, Berry G J, Huang X, Shorthouse R, Brazelton T, Morris R E. Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts.  Transplantation. 2000;  69 2260-2266
    PubMedGoogle Scholar
  • 17 Fahrni J A, Berry G J, Morris R E, Rosen G D. Rapamycin inhibits development of obliterative airway disease in a murine heterotopic airway transplant model.  Transplantation. 1997;  63 533-537
    PubMedGoogle Scholar
  • 18 Schrepfer S, Deuse T, Sydow K, Schafer H, Detter C, Reichenspurner H. Tracheal allograft transplantation in rats: the role of different immunosuppressants on preservation of respiratory epithelium.  Transplant Proc. 2006;  38 741-744
    CrossrefPubMedGoogle Scholar
  • 19 Hashimoto M, Nakanishi R, Muranaka H, Umesue M, Eifuku R, Yasumoto K. Short-course immunosuppression using FK506 for rat tracheal allografts.  J Cardiovasc Surg (Torino). 2000;  41 487-492
    PubMedGoogle Scholar
  • 20 Nakashima S, Soong T R, Fox-Talbot K et al.. Impact of MHC class II incompatibility on localization of mononuclear cell infiltrates to the bronchiolar compartment of orthotopic lung allografts.  Am J Transplant. 2005;  5(4 Pt 1) 694-701
    CrossrefPubMedGoogle Scholar
  • 21 Shoji T, Wain J C, Houser S L et al.. Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.  Am J Transplant. 2005;  5 1626-1634
    CrossrefPubMedGoogle Scholar
  • 22 Warnecke G, Avsar M, Steinkamp T et al.. Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine.  Eur J Cardiothorac Surg. 2005;  28 454-460
    CrossrefPubMedGoogle Scholar
  • 23 Shoji T, Muniappan A, Guenther D A et al.. Long-term acceptance of porcine pulmonary allografts without chronic rejection.  Transplant Proc. 2005;  37 72-74
    CrossrefPubMedGoogle Scholar
  • 24 Schulman L L, Weinberg A D, McGregor C C, Suciu-Foca N M, Itescu S. Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation.  Am J Respir Crit Care Med. 2001;  163 437-442
    PubMedGoogle Scholar
  • 25 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
    CrossrefPubMedGoogle Scholar
  • 26 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
    CrossrefPubMedGoogle Scholar
  • 27 van den Berg J W, Hepkema B G, Geertsma A et al.. Long-term outcome of lung transplantation is predicted by the number of HLA-DR mismatches.  Transplantation. 2001;  71 368-373
    CrossrefPubMedGoogle Scholar
  • 28 Wisser W, Wekerle T, Zlabinger G et al.. Influence of human leukocyte antigen matching on long-term outcome after lung transplantation.  J Heart Lung Transplant. 1996;  15 1209-1216
    PubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Schulman L L, Weinberg A D, McGregor C, Galantowicz M E, Suciu-Foca N M, Itescu S. Mismatches at the HLA-DR and HLA-B loci are risk factors for acute rejection after lung transplantation.  Am J Respir Crit Care Med. 1998;  157(6 Pt 1) 1833-1837
    PubMedGoogle Scholar
  • 31 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
    CrossrefPubMedGoogle Scholar
  • 32 Reinsmoen N L, Bolman R M, Savik K, Butters K, Matas A J, Hertz M I. Improved long-term graft outcome in lung transplant recipients who have donor antigen-specific hyporeactivity.  J Heart Lung Transplant. 1994;  13(1 Pt 1) 30-36 discussion 36-37
    PubMedGoogle Scholar
  • 33 Reznik S I, Jaramillo A, SivaSai K S et al.. Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome.  Am J Transplant. 2001;  1 228-235
    CrossrefPubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar
  • 35 Charo I F, Ransohoff R M. The many roles of chemokines and chemokine receptors in inflammation.  N Engl J Med. 2006;  354 610-621
    CrossrefPubMedGoogle Scholar
  • 36 Belperio J A, Keane M P, Burdick M D et al.. CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury.  J Immunol. 2005;  175 6931-6939
    PubMedGoogle Scholar
  • 37 De Perrot M, Sekine Y, Fischer S et al.. Interleukin-8 release during early reperfusion predicts graft function in human lung transplantation.  Am J Respir Crit Care Med. 2002;  165 211-215
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Tan J, Zhou G. Chemokine receptors and transplantation.  Cell Mol Immunol. 2005;  2 343-349
    PubMedGoogle Scholar
  • 40 Agostini C, Calabrese F, Rea F et al.. CXCR3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection.  Am J Pathol. 2001;  158 1703-1711
    PubMedGoogle Scholar
  • 41 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
    PubMedGoogle Scholar
  • 42 Medoff B D, Wain J C, Seung E et al.. CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function.  J Immunol. 2006;  176 7087-7095
    PubMedGoogle Scholar
  • 43 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
    CrossrefPubMedGoogle Scholar
  • 44 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
    CrossrefPubMedGoogle Scholar
  • 45 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
    PubMedGoogle Scholar
  • 46 Suga M, Maclean A A, Keshavjee S, Fischer S, Moreira J M, Liu M. RANTES plays an important role in the evolution of allograft transplant-induced fibrous airway obliteration.  Am J Respir Crit Care Med. 2000;  162 1940-1948
    PubMedGoogle Scholar
  • 47 Hodge G, Hodge S, Reynolds P N, Holmes M. Up-regulation of interleukin-8, interleukin-10, monocyte chemotactic protein-1, and monocyte chemotactic protein-3 in peripheral blood monocytes in stable lung transplant recipients: are immunosuppression regimens working?.  Transplantation. 2005;  79 387-391
    CrossrefPubMedGoogle Scholar
  • 48 Crespo M, Pascual M, Tolkoff-Rubin N et al.. Acute humoral rejection in renal allograft recipients, I: Incidence, serology and clinical characteristics.  Transplantation. 2001;  71 652-658
    PubMedGoogle Scholar
  • 49 Racusen L C, Colvin R B, Solez K et al.. Antibody-mediated rejection criteria: an addition to the Banff 97 classification of renal allograft rejection.  Am J Transplant. 2003;  3 708-714
    CrossrefPubMedGoogle Scholar
  • 50 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
    CrossrefPubMedGoogle Scholar
  • 51 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
    CrossrefPubMedGoogle Scholar
  • 52 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
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 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(Suppl 7) S249-S254
    CrossrefPubMedGoogle Scholar
  • 55 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
    PubMedGoogle Scholar
  • 56 Badesch D B, Zamora M, Fullerton D et al.. Pulmonary capillaritis: a possible histologic form of acute pulmonary allograft rejection.  J Heart Lung Transplant. 1998;  17 415-422
    PubMedGoogle Scholar
  • 56a Magro C M, Deng A, Pope-Harman A et al.. Humorally mediated postransplantation septal capillary injury syndrom as a common from of pulmonary allogtaft rejection: a hypothesis.  Transplantation. 2002;  74 1273-1280
    CrossrefPubMedGoogle Scholar
  • 57 Saint Martin G A, Reddy V B, Garrity E R et al.. Humoral (antibody-mediated) rejection in lung transplantation.  J Heart Lung Transplant. 1996;  15 1217-1222
    PubMedGoogle Scholar
  • 58 Jaramillo A, Naziruddin B, Zhang L et al.. Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: a potential etiological factor for bronchiolitis obliterans syndrome.  Transplantation. 2001;  71 966-976
    PubMedGoogle Scholar
  • 59 Magro C M, Pope Harman A, Klinger D et al.. Use of C4d as a diagnostic adjunct in lung allograft biopsies.  Am J Transplant. 2003;  3 1143-1154
    CrossrefPubMedGoogle Scholar
  • 60 Magro C M, Ross Jr P, Kelsey M, Waldman W J, Pope-Harman A. Association of humoral immunity and bronchiolitis obliterans syndrome.  Am J Transplant. 2003;  3 1155-1166
    CrossrefPubMedGoogle Scholar
  • 61 Magro C M, Abbas A E, Seilstad K, Pope-Harman A L, Nadasdy T, Ross Jr P. C3d and the septal microvasculature as a predictor of chronic lung allograft dysfunction.  Hum Immunol. 2006;  67 274-283
    CrossrefPubMedGoogle Scholar
  • 62 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
    PubMedGoogle Scholar
  • 63 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
    CrossrefPubMedGoogle Scholar
  • 64 Yasufuku K, Heidler K M, O'Donnell P W et al.. Oral tolerance induction by type V collagen downregulates lung allograft rejection.  Am J Respir Cell Mol Biol. 2001;  25 26-34
    PubMedGoogle Scholar
  • 65 Yasufuku K, Heidler K M, Woods K A et al.. Prevention of bronchiolitis obliterans in rat lung allografts by type V collagen-induced oral tolerance.  Transplantation. 2002;  73 500-505
    CrossrefPubMedGoogle Scholar
  • 66 Wood K J, Sakaguchi S. Regulatory T cells in transplantation tolerance.  Nat Rev Immunol. 2003;  3 199-210
    CrossrefPubMedGoogle Scholar
  • 67 Muthukumar T, Dadhania D, Ding R et al.. Messenger RNA for FOXP3 in the urine of renal-allograft recipients.  N Engl J Med. 2005;  353 2342-2351
    CrossrefPubMedGoogle Scholar
  • 68 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
    CrossrefPubMedGoogle Scholar
  • 69 Levings M K, Sangregorio R, Roncarolo M G. Human CD25(+) CD4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function.  J Exp Med. 2001;  193 1295-1302
    CrossrefPubMedGoogle Scholar
  • 70 Zhang X, Izikson L, Liu L, Weiner H L. Activation of CD25(+) CD4(+) regulatory T cells by oral antigen administration.  J Immunol. 2001;  167 4245-4253
    PubMedGoogle Scholar
  • 71 Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity.  Adv Exp Med Biol. 2005;  560 11-18
    PubMedGoogle Scholar
  • 72 Akira S, Takeda K. Toll-like receptor signalling.  Nat Rev Immunol. 2004;  4 499-511
    CrossrefPubMedGoogle Scholar
  • 73 Goldstein D R, Tesar B M, Akira S, Lakkis F G. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection.  J Clin Invest. 2003;  111 1571-1578
    CrossrefPubMedGoogle Scholar
  • 74 Goldstein D R. Toll-like receptors and other links between innate and acquired alloimmunity.  Curr Opin Immunol. 2004;  16 538-544
    CrossrefPubMedGoogle Scholar
  • 75 Arbour N C, Lorenz E, Schutte B C et al.. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.  Nat Genet. 2000;  25 187-191
    CrossrefPubMedGoogle Scholar
  • 76 Palmer S M, Burch L H, Davis R D et al.. The role of innate immunity in acute allograft rejection after lung transplantation.  Am J Respir Crit Care Med. 2003;  168 628-632
    CrossrefPubMedGoogle Scholar
  • 77 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
    CrossrefPubMedGoogle Scholar
  • 78 Hohlfeld J M, Tiryaki E, Hamm H et al.. Pulmonary surfactant activity is impaired in lung transplant recipients.  Am J Respir Crit Care Med. 1998;  158 706-712
    PubMedGoogle Scholar
  • 79 Lehrer R I, Ganz T. Endogenous vertebrate antibiotics: defensins, protegrins, and other cysteine-rich antimicrobial peptides.  Ann NY Acad Sci. 1996;  797 228-239
    PubMedGoogle Scholar
  • 80 Schutte B C, McCray Jr P B. [βeta]-defensins in lung host defense.  Annu Rev Physiol. 2002;  64 709-748
    CrossrefPubMedGoogle Scholar
  • 81 Nelsestuen G L, Martinez M B, Hertz M I, Savik K, Wendt C H. Proteomic identification of human neutrophil alpha-defensins in chronic lung allograft rejection.  Proteomics. 2005;  5 1705-1713
    CrossrefPubMedGoogle Scholar
  • 82 Yang D, Chertov O, Bykovskaia S N et al.. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.  Science. 1999;  286 525-528
    CrossrefPubMedGoogle Scholar
  • 83 Biragyn A, Ruffini P A, Leifer C A et al.. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2.  Science. 2002;  298 1025-1029
    CrossrefPubMedGoogle Scholar
  • 84 Harder J, Meyer-Hoffert U, Teran L M et al.. Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia.  Am J Respir Cell Mol Biol. 2000;  22 714-721
    PubMedGoogle Scholar
  • 85 Ross D J, Cole A M, Yoshioka D et al.. Increased bronchoalveolar lavage human beta-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation.  Transplantation. 2004;  78 1222-1224
    PubMedGoogle Scholar

Laurie D SnyderM.D. 

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center

DUMC 3876, Durham, NC 27710

eMail: laurie.snyder@duke.edu