Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation
2016; Elsevier BV; Volume: 35; Issue: 4 Linguagem: Inglês
10.1016/j.healun.2016.01.1223
ISSN1557-3117
AutoresDeborah J. Levine, Allan R. Glanville, Christina Aboyoun, John A. Belperio, Christian Benden, Gerald J. Berry, Ramsey R. Hachem, Don Hayes, Desley Neil, Nancy L. Reinsmoen, Laurie D. Snyder, Stuart C. Sweet, Dolly B. Tyan, Geert M. Verleden, Glen P. Westall, Roger D. Yusen, Martin R. Zamora, Adriana Zeevi,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoAntibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications. Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications. Donor-specific anti–human leukocyte antigen (HLA) antibodies (DSA), are known to contribute to antibody-mediated rejection (AMR) in solid-organ transplantation.1Hachem R.R. Yusen R.D. Meyers B.F. et al.Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation.J Heart Lung Transplant. 2010; 29: 973-980Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 2Lobo L.J. Aris R.M. Schmitz J. et al.Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation.J Heart Lung Transplant. 2013; 32: 70-77Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar The best-characterized donor antigens are HLA, which are further divided, based on their structure and function, into HLA Class I and Class II. The presence of DSA at the time of transplant or detected de novo post-transplant is well described in renal transplantation, where it has been associated with compromised renal allograft survival.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar, 4Lefaucheur C. Loupy A. Hill G.S. et al.Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.J Am Soc Nephrol. 2010; 21: 1398-1406Crossref PubMed Scopus (628) Google Scholar, 5Singh N. Djamali A. Lorentzen D. et al.Pretransplant donor-specific antibodies detected by single-antigen bead flow cytometry are associated with inferior kidney transplant outcomes.Transplantation. 2010; 90: 1079-1084Crossref PubMed Scopus (63) Google Scholar, 6Wiebe C. Gibson I.W. Blydt-Hansen T.D. et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.Am J Transplant. 2012; 12: 1157-1167Crossref PubMed Scopus (726) Google Scholar De novo DSA and an increase in DSA titers, perhaps via an anamnestic response, have also been associated with lung allograft dysfunction, occasionally in asymptomatic patients.1Hachem R.R. Yusen R.D. Meyers B.F. et al.Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation.J Heart Lung Transplant. 2010; 29: 973-980Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 7Morrell M.R. Pilewski J.M. Gries C.J. et al.De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation.J Heart Lung Transplant. 2014; 33: 1288-1294Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Safavi S. Robinson D.R. Soresi S. et al.De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation.J Heart Lung Transplant. 2014; 33: 1273-1281Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar However, there is no agreed-upon definition for pulmonary AMR in the literature. AMR is a complex pathologic, serologic and clinical process that is well recognized in kidney and heart allografts but ill-defined in lung transplantation. A process of immune activation, whereby allospecific B-cells and plasma cells produce antibodies directed against donor lung antigens, is central to the concept of pulmonary AMR. The antigen–antibody complex results in an amplified immune response, via both complement-dependent and independent pathways, which results in lung tissue pathology and graft dysfunction to a variable degree. Complement is a multifunctional system of receptors, regulators and effector molecules that may amplify both innate and adaptive immunity contributing to the pathogenesis of AMR.9Baldwin 3rd, W.M. Kasper E.K. Zachary A.A. et al.Beyond C4d: other complement-related diagnostic approaches to antibody-mediated rejection.Am J Transplant. 2004; 4: 311-318Crossref PubMed Scopus (64) Google Scholar To date, individual transplant centers have defined AMR uniquely, making it difficult to interpret studies and to compare strategies and outcomes between centers. A standardized definition is therefore required to: facilitate interpretation of the available literature; diagnose specific cases; develop treatment options; and inform research via identification of risk factors, incidence, prevalence, clinical course and prognosis. Most importantly, an agreed-upon definition with a universal nomenclature facilitates the conversation between user groups to improve collection of outcome data and allows comparison of treatment regimens and, ultimately, the creation and standardization of therapeutic guidelines, as recently described for the bronchiolitis obliterans syndrome (BOS).10Meyer K.C. Raghu G. Verleden G.M. et al.An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (366) Google Scholar The primary aim was to reach a consensus on a formal working definition of pulmonary AMR. Secondary goals were to propose phenotypes of pulmonary AMR and identify knowledge gaps on topics related to pulmonary AMR to direct clinical evaluation and future research. The major immunologic advances in the past decade in AMR in solid-organ transplantation have been implementation of sensitive and specific solid-phase assays for identification of DSA, improved understanding of the pathogenic effect of alloantibodies, and integration of molecular transcripts to better define the spectrum of graft injury mediated by alloantibody.11Halloran P.F. Reeve J.P. Pereira A.B. et al.Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.Kidney Int. 2014; 85: 258-264Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 12Loupy A. Hill G.S. Jordan S.C. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure.Nat Rev Nephrol. 2012; 8: 348-357Crossref PubMed Scopus (273) Google Scholar, 13Tait B.D. Susal C. Gebel H.M. et al.Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.Transplantation. 2013; 95: 19-47Crossref PubMed Scopus (599) Google Scholar More recently, the use of molecular transcripts has demonstrated that microvascular inflammation without C4d staining may be an indicator of AMR in both kidney and cardiac allografts.14Haas M. Sis B. Racusen L.C. et al.Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14: 272-283Crossref PubMed Scopus (1063) Google Scholar DSA have been associated with acute allograft rejection in kidney, heart and lung allografts.2Lobo L.J. Aris R.M. Schmitz J. et al.Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation.J Heart Lung Transplant. 2013; 32: 70-77Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 11Halloran P.F. Reeve J.P. Pereira A.B. et al.Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.Kidney Int. 2014; 85: 258-264Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 15Zeevi A. Lunz J. Feingold B. et al.Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients.J Heart Lung Transplant. 2013; 32: 98-105Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Importantly, DSA have also been associated with chronic allograft rejection, as manifested by transplant glomerulopathy in kidney recipients, cardiac allograft vasculopathy in heart recipients and obliterative bronchiolitis (OB) in lung transplant recipients.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar, 8Safavi S. Robinson D.R. Soresi S. et al.De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation.J Heart Lung Transplant. 2014; 33: 1273-1281Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 15Zeevi A. Lunz J. Feingold B. et al.Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients.J Heart Lung Transplant. 2013; 32: 98-105Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 16Russell P.S. Chase C.M. Winn H.J. et al.Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity.J Immunol. 1994; 152: 5135-5141PubMed Google Scholar Although DSA have been shown to appear before loss of lung function and are predictive of poor outcomes, controversy continues regarding: whether antibodies detected solely by highly sensitive techniques are clinically relevant; how to monitor post-transplant; and when to implement antibody-removal therapies in the absence of clinical dysfunction.1Hachem R.R. Yusen R.D. Meyers B.F. et al.Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation.J Heart Lung Transplant. 2010; 29: 973-980Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 7Morrell M.R. Pilewski J.M. Gries C.J. et al.De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation.J Heart Lung Transplant. 2014; 33: 1288-1294Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Safavi S. Robinson D.R. Soresi S. et al.De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation.J Heart Lung Transplant. 2014; 33: 1273-1281Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Notably, DSA level and function should not be assessed by the mean fluorescent intensity (MFI) of the single antigen bead (SAB) assay, because the MFI does not represent the titer of circulating HLA antibody. It is the titer, not the MFI per se, that is indicative of antibody load. Furthermore, the presence of strongly binding antibodies may be underestimated due to inhibition by IgM or the C1 component of complement in undiluted sera.13Tait B.D. Susal C. Gebel H.M. et al.Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.Transplantation. 2013; 95: 19-47Crossref PubMed Scopus (599) Google Scholar, 17Schnaidt M. Weinstock C. Jurisic M. et al.HLA antibody specification using single-antigen beads—a technical solution for the prozone effect.Transplantation. 2011; 92: 510-515Crossref PubMed Scopus (174) Google Scholar The clinical relevance of DSA may depend on immunoglobulin G (IgG) subclass. Complement-fixing IgG (IgG1/IgG3) may be more damaging than non–complement-fixing IgG (IgG2/IgG4). However, IgG2 and IgG4 antibodies may also exert damaging effects by mechanisms other than complement activation. Modification of the SAB assay to detect complement binding (C1q assay) has provided a new tool for possible risk stratification of transplant recipients who exhibit DSA.18Tyan D.B. New approaches for detecting complement-fixing antibodies.Curr Opin Organ Transplant. 2012; 17: 409-415Crossref PubMed Scopus (24) Google Scholar In cardiac transplantation, correlations have been demonstrated between C1q-positive antibodies and early AMR, and in renal transplants the presence of complement-binding DSA has been associated with a more severe graft injury phenotype and a significant risk for graft failure.15Zeevi A. Lunz J. Feingold B. et al.Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients.J Heart Lung Transplant. 2013; 32: 98-105Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 19Loupy A. Lefaucheur C. Vernerey D. et al.Complement-binding anti-HLA antibodies and kidney-allograft survival.N Engl J Med. 2013; 369: 1215-1226Crossref PubMed Scopus (648) Google Scholar Similarly, in lung transplant recipients, the presence of Class II, C1q-binding antibody has been associated with allograft injury and high-grade acute cellular rejection (ACR).20Yousem S.A. Zeevi A. The histopathology of lung allograft dysfunction associated with the development of donor-specific HLA alloantibodies.Am J Surg Pathol. 2012; 36: 987-992Crossref PubMed Scopus (43) Google Scholar Furthermore, although the presence of capillary C4d staining in alveolar tissue may support the presence of an antibody-mediated process, other etiologies, including procurement injury (e.g., acute alveolar injury after ischemia/reperfusion), high-grade ACR and infection, need to be considered in the differential diagnosis.20Yousem S.A. Zeevi A. The histopathology of lung allograft dysfunction associated with the development of donor-specific HLA alloantibodies.Am J Surg Pathol. 2012; 36: 987-992Crossref PubMed Scopus (43) Google Scholar Extensive individual experience with protocol C4d staining of lung, heart, liver and kidney transplant biopsies improves the ability to discriminate confounding variables. Positive lung C4d staining in high-grade rejection may in fact represent mixed ACR and AMR rather than artifact. The presence of high natural killer (NK) transcripts in many AMR renal biopsies supports the concept of the role of NK cells in mediating allograft injury. NK cells in the vascular lumen recognize antibody on the cell surface through their Fc-receptor, CD16, leading to increased interferon-gamma (IFN-γ) production. The inflammatory effects of IFN-γ are manifested by increased major histocompatibility complex (MHC) expression on endothelial cells and activation of monocytes.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar, 11Halloran P.F. Reeve J.P. Pereira A.B. et al.Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.Kidney Int. 2014; 85: 258-264Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Furthermore, in the presence of DSA that activate complement (IgG1/IgG3), the inflammatory response includes both activated NK and monocytes. With non–complement-binding DSA (IgG2/IgG4), the inflammatory response is limited to monocyte infiltration.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar Thus, graft injury in the presence of complement-binding DSA, especially of the IgG3 subtype, is induced by the cytotoxic effects of complement-activating antibody and by the induction of cellular effector mechanisms mediated by activated NK cells and monocytes. In summary, there are now improved techniques available for determining DSA specificity, level and function. Using these refined assays we can better detect DSA, improve risk stratification, and intervene earlier with the hope of improving long-term allograft survival. In the 1970s, early investigations into AMR demonstrated that antibodies with or without a cellular response could lead to a vasculopathy. Stronger evidence linking antibodies with allograft damage was provided in murine cardiac chronic rejection models by Russell et al,16Russell P.S. Chase C.M. Winn H.J. et al.Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity.J Immunol. 1994; 152: 5135-5141PubMed Google Scholar who found, using Class I–mismatched strain combinations, that only recipients with complement-dependent cytotoxic antibodies developed a severe vasculopathy.16Russell P.S. Chase C.M. Winn H.J. et al.Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity.J Immunol. 1994; 152: 5135-5141PubMed Google Scholar Multiple investigations using both in vitro and in vivo studies have demonstrated that MHC ligation can lead to complement-dependent mechanisms with (classical and lectin pathways) and without (alternative pathway) C4d deposition that damage the allograft.21Murata K. Baldwin III, W.M. Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection.Transplant Rev (Orlando). 2009; 23: 139-150Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 22Kuo H.H. Morrell C.N. Baldwin III, W.M. Alloantibody induced platelet responses in transplants: potent mediators in small packages.Hum Immunol. 2012; 73: 1233-1238Crossref Scopus (13) Google Scholar, 23Wasowska B.A. Mechanisms involved in antibody- and complement-mediated allograft rejection.Immunol Res. 2010; 47: 25-44Crossref PubMed Scopus (41) Google Scholar Furthermore, MHC ligation of endothelial cells with and without the help of integrin-β4 can lead to a vasculopathy through complement-independent mechanisms that include: (a) signaling cascades, such as FAK, SCR, PI3k, AKT, mTORC1 [(Raptor) GbL (mTOR)], S6k and S6RP, which cause endothelial/smooth muscle cells to proliferate and release inflammatory mediators; (b) exocytosis of granules containing von Willebrand factor (vWF) and P-selectin, which cause platelet activation and inflammation; (c) up-regulation of fibroblast-like growth factor receptor (FGFR)/FGF biology and its downstream MEK and ERK pathways leading to endothelial/smooth muscle cell proliferation; and (d) up-regulation of endothelial cell expression of chemokines, which recruit NK cells that express IFN-γ–inducing cells to express more MHC Class I and II, generating further alloimmunity.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar, 21Murata K. Baldwin III, W.M. Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection.Transplant Rev (Orlando). 2009; 23: 139-150Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 22Kuo H.H. Morrell C.N. Baldwin III, W.M. Alloantibody induced platelet responses in transplants: potent mediators in small packages.Hum Immunol. 2012; 73: 1233-1238Crossref Scopus (13) Google Scholar, 23Wasowska B.A. Mechanisms involved in antibody- and complement-mediated allograft rejection.Immunol Res. 2010; 47: 25-44Crossref PubMed Scopus (41) Google Scholar, 24Akiyoshi T. Hirohashi T. Alessandrini A. et al.Role of complement and NK cells in antibody mediated rejection.Hum Immunol. 2012; 73: 1226-1232Crossref PubMed Scopus (54) Google Scholar, 25Dragun D. Catar R. Kusch A. et al.Non-HLA-antibodies targeting angiotensin type 1 receptor and antibody mediated rejection.Hum Immunol. 2012; 73: 1282-1286Crossref PubMed Scopus (43) Google Scholar, 26Li F. Zhang X. Jin Y.P. et al.Antibody ligation of human leukocyte antigen class I molecules stimulates migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner.Hum Immunol. 2011; 72: 1150-1159Crossref PubMed Scopus (35) Google Scholar, 27Sis B. Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection.Hum Immunol. 2012; 73: 1218-1225Crossref PubMed Scopus (21) Google Scholar, 28Trayssac M. Negre-Salvayre A. Thomsen M. Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.Hum Immunol. 2012; 73: 1253-1260Crossref PubMed Scopus (6) Google Scholar, 29Zhang X. Valenzuela N.M. Reed E.F. HLA class I antibody-mediated endothelial and smooth muscle cell activation. Curr Opin.Organ Transplant. 2012; 17: 446-451Crossref PubMed Scopus (23) Google Scholar, 30Tsai E.W. Reed E.F. MHC class I signaling: new functional perspectives for an old molecule.Tissue Antigens. 2014; 83: 375-381Crossref Scopus (8) Google Scholar, 31Valenzuela N.M. McNamara J.T. Reed E.F. Antibody-mediated graft injury: complement-dependent and complement-independent mechanisms.Curr Opin Organ Transplant. 2014; 19: 33-40Crossref PubMed Scopus (80) Google Scholar Alternatively, the Fc portion of antibodies can interact with leukocytes via Fc-receptors (FcR) initiating antibody-dependent cellular cytotoxicity (ADCC), opsonization and cytokine/chemokine expression, all of which exaggerate allograft damage.3Hidalgo L.G. Campbell P.M. Sis B. et al.De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Crossref PubMed Scopus (251) Google Scholar, 21Murata K. Baldwin III, W.M. Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection.Transplant Rev (Orlando). 2009; 23: 139-150Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 22Kuo H.H. Morrell C.N. Baldwin III, W.M. Alloantibody induced platelet responses in transplants: potent mediators in small packages.Hum Immunol. 2012; 73: 1233-1238Crossref Scopus (13) Google Scholar, 23Wasowska B.A. Mechanisms involved in antibody- and complement-mediated allograft rejection.Immunol Res. 2010; 47: 25-44Crossref PubMed Scopus (41) Google Scholar, 24Akiyoshi T. Hirohashi T. Alessandrini A. et al.Role of complement and NK cells in antibody mediated rejection.Hum Immunol. 2012; 73: 1226-1232Crossref PubMed Scopus (54) Google Scholar, 25Dragun D. Catar R. Kusch A. et al.Non-HLA-antibodies targeting angiotensin type 1 receptor and antibody mediated rejection.Hum Immunol. 2012; 73: 1282-1286Crossref PubMed Scopus (43) Google Scholar, 26Li F. Zhang X. Jin Y.P. et al.Antibody ligation of human leukocyte antigen class I molecules stimulates migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner.Hum Immunol. 2011; 72: 1150-1159Crossref PubMed Scopus (35) Google Scholar, 27Sis B. Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection.Hum Immunol. 2012; 73: 1218-1225Crossref PubMed Scopus (21) Google Scholar, 28Trayssac M. Negre-Salvayre A. Thomsen M. Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.Hum Immunol. 2012; 73: 1253-1260Crossref PubMed Scopus (6) Google Scholar, 29Zhang X. Valenzuela N.M. Reed E.F. HLA class I antibody-mediated endothelial and smooth muscle cell activation. Curr Opin.Organ Transplant. 2012; 17: 446-451Crossref PubMed Scopus (23) Google Scholar Last, autoantibodies (e.g., vimentin, collagen V, perlecan, Kα1-tubulin, AT1R and MICA) can also cause significant allograft damage as well as amplify alloantibody damage.25Dragun D. Catar R. Kusch A. et al.Non-HLA-antibodies targeting angiotensin type 1 receptor and antibody mediated rejection.Hum Immunol. 2012; 73: 1282-1286Crossref PubMed Scopus (43) Google Scholar, 32Sarma N.J. Tiriveedhi V. Angaswamy N. et al.Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications.Hum Immunol. 2012; 73: 1275-1281Crossref Scopus (10) Google Scholar, 33Tiriveedhi V. Takenaka M. Sarma N.J. et al.Anti-major histocompatibility complex–induced obliterative airway disease: selective role for CD4 and CD8 T cells in inducing immune responses to self-antigens.J Heart Lung Transplant. 2013; 32: 714-722Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In murine models, intrabronchial administration of anti-MHC Class I or II antibodies can upregulate autoimmunity, leading to OB.34Takenaka M. Tiriveedhi V. Subramanian V. et al.Antibodies to MHC class II molecules induce autoimmunity: critical role for macrophages in the immunopathogenesis of obliterative airway disease.PLoS One. 2012; 7: e42370Crossref PubMed Scopus (23) Google Scholar, 35Fukami N. Ramachandran S. Saini D. et al.Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection.J Immunol. 2009; 182: 309-318Crossref PubMed Scopus (138) Google Scholar Together, these studies showed that antibodies can lead to lung injury via multiple mechanisms, including complement-independent as well as complement-dependent direct damage. However, there are some antibodies (class- and titer-dependent) that may help with allograft accommodation.36Charreau B. Signaling of endothelial cytoprotection in transplantation.Hum Immunol. 2012; 73: 1245-1252Crossref Scopus (6) Google Scholar Future studies should determine the balance of antibodies with regard to titer and class as well as molecular mechanisms that determine overall allograft outcomes. The Pathology Council summarized the current understanding of the pathology of pulmonary AMR following consensus discussions at the annual scientific meeting of the International Society for Heart and Lung Transplantation (ISHLT) in 2012.37Berry G. Burke M. Andersen C. et al.Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT.J Heart Lung Transplant. 2013; 32: 14-21Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Histopathologic features, including neutrophil margination, neutrophil capillaritis and arteritis, are non-specific, as they may be seen in other forms of lung injury, as can organizing pneumonia. Immunohistochemistry for C4d, either by immunofluorescence (IF) or immunoperoxidase (IP) assays, may provide supportive evidence of AMR. A survey of histopathologists was undertaken before the meeting. Based on the aforementioned criteria, histopathologic and immunohistochemical evidence of AMR was uncommon. It was agreed that the histopathologic features outlined in the 2013 report were still valid, and, based on current knowledge, need refining. However, the sensitivity of C4d staining was questioned in line with developments in the renal literature, where it is no longer an obligate criterion of AMR. As there are only a small number of AMR cases that meet all the criteria (positive DSA, graft dysfunction, histopathologic features and C4d positivity), the experience of any individual pathologist must perforce be limited. Hence, cases of pulmonary AMR meeting these criteria are being gathered and scanned and made available online as digital whole slide images for group assessment. It has been proposed to gather a set of C4d-positive cases with enough material to be able to create a tissue microarray enabling the methods of different laboratories to be compared so we may confirm that the apparent lack of C4d-positive cases is not due to methodologic problems.38Roden A.C. Maleszewski J.J. Yi E.S. et al.Reproducibility of complement 4d deposition by immunofluorescence and immunohistochemistry in lung allograft biopsies.J Heart Lung Transplant. 2014; 33: 1223-1232Abstract
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