Immune Mechanisms of Lung Allograft Rejection

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.

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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 39 Tan J, Zhou G. Chemokine receptors and transplantation.  Cell Mol Immunol. 2005;  2 343-349
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 66 Wood K J, Sakaguchi S. Regulatory T cells in transplantation tolerance.  Nat Rev Immunol. 2003;  3 199-210
• 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
• 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
• 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
• 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
• 71 Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity.  Adv Exp Med Biol. 2005;  560 11-18
• 72 Akira S, Takeda K. Toll-like receptor signalling.  Nat Rev Immunol. 2004;  4 499-511
• 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
• 74 Goldstein D R. Toll-like receptors and other links between innate and acquired alloimmunity.  Curr Opin Immunol. 2004;  16 538-544
• 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
• 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
• 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
• 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
• 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
• 80 Schutte B C, McCray Jr P B. [βeta]-defensins in lung host defense.  Annu Rev Physiol. 2002;  64 709-748
• 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
• 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
• 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
• 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
• 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