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• W2521101777 abstract "A third of lung recipients have preexisting antibodies against nonhuman leukocyte self-antigens (nHAbs) present in the lung tissue. These nHAbs also form de novo in about 70% of patients within 3 years after transplantation. Both preexisting and de novo nHAbs can cause murine lung allograft dysfunction. However, their role in human transplantation remains unclear. We report hyperacute rejection after right lung transplant in a recipient with preexisting nHAbs. The recipient of the left lung from the same donor had an uneventful initial course, but de novo nHAbs developed at 3 weeks, leading to acute humoral rejection. Both patients were successfully treated with antibody-directed therapies. A third of lung recipients have preexisting antibodies against nonhuman leukocyte self-antigens (nHAbs) present in the lung tissue. These nHAbs also form de novo in about 70% of patients within 3 years after transplantation. Both preexisting and de novo nHAbs can cause murine lung allograft dysfunction. However, their role in human transplantation remains unclear. We report hyperacute rejection after right lung transplant in a recipient with preexisting nHAbs. The recipient of the left lung from the same donor had an uneventful initial course, but de novo nHAbs developed at 3 weeks, leading to acute humoral rejection. Both patients were successfully treated with antibody-directed therapies. Damage attributable to the underlying lung disease can expose “sequestered” nonhuman leukocyte tissue–restricted self-antigens (sAgs), resulting in autoantibody development in the host [1Kheradmand F. Shan M. Xu C. Corry D.B. Autoimmunity in chronic obstructive pulmonary disease: clinical and experimental evidence.Expert Rev Clin Immunol. 2012; 8: 285-292Crossref Scopus (68) Google Scholar]. We have previously shown that up to one third of lung recipients with end-stage lung disease have such preexisting nonhuman leukocyte antibodies (nHAbs) [2Bharat A. Kuo E. Saini D. et al.Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection.Ann Thorac Surg. 2010; 90 (discussion 1644): 1637-1644Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Self-antigens, unlike HLA antigens, are nonpolymorphic and do not differ between individuals within a species [3Guerder S. Viret C. Luche H. Ardouin L. Malissen B. Differential processing of self-antigens by subsets of thymic stromal cells.Curr Opin Immunol. 2012; 24: 99-104Crossref PubMed Scopus (17) Google Scholar]. Self-antigens are normally hidden, but ischemia-reperfusion to the allograft can reveal them to the recipient’s immune system. Hence, preexisting nHAbs in a recipient can bind to sAgs in the allograft after transplantation. The current crossmatch technique uses donor lymphocytes that do not express tissue-restricted sAgs and therefore does not detect preexisting autoantibodies. Therefore, hyperacute rejection may occur as a result of preexisting nHAbs despite negative crossmatch result. In patients who do not have preexisting nHAbs, de novo nHAbs can develop after lung transplantation [4Hachem R.R. Tiriveedhi V. Patterson G.A. et al.Antibodies to K-alpha 1 tubulin and collagen V are associated with chronic rejection after lung transplantation.Am J Transplant. 2012; 12: 2164-2171Crossref PubMed Scopus (119) Google Scholar]. The development of these new antibodies, which are of the immunoglobulin-G (IgG) class, takes about 2 to 3 weeks after antigenic exposure. The de novo nHAbs can mediate acute antibody-mediated rejection (AMR) after lung transplantation. Accordingly, we demonstrate, for the first time, the development of hyperacute rejection and AMR in two recipients with preexisting and de novo nHAbs, respectively. The donor was a brain-dead 26-year-old nonsmoking man with a gunshot wound to the head. Chest imaging, bronchoscopy, and lung function were normal. Procurement was performed by two attending thoracic surgeons from Northwestern University and Cleveland Clinic Foundation. Recipient 1: The recipient of the right lung was a 53-year-old woman with emphysema and normal pulmonary pressures who underwent transplantation without cardiopulmonary bypass. Induction immunosuppression consisted of methylprednisolone (500 mg) and basiliximab (20 mg). Panel-reactive HLA antibodies (PRA) were not detected; the results of T-lymphocyte and B-lymphocyte cross-matches were negative. Implantation was uncomplicated, with 243 minutes of total and 39 minutes of warm ischemia. After reperfusion, the recipient had a PaO2 of 155 mm Hg on 30% inspired oxygen (FiO2). Transesophageal echocardiography revealed normal flow velocities across the vascular anastomoses. Thirty minutes after reperfusion, the allograft became acutely congested, and the patient required 100% FiO2 to maintain a PaO2 above 70 mm Hg. Chest radiography revealed dense infiltrates in the allograft (Figs 1A, 1B ). Contrast computed tomography did not show fat or thromboembolism. Transbronchial allograft biopsy on day 1 demonstrated septal neutrophils, diffuse alveolar damage, hyaline membrane formation (Fig 1C), and complement (C4D) deposition (Fig 2B), consistent with antibody-mediated rejection (AMR), as proposed by ISHLT Pathology Council of the International Society for Heart and Lung Transplantation [5Berry 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 (96) Google Scholar]. Furthermore, IgG deposition was noted (Fig 2A). There was no growth of bacteria, fungi, or viruses in the bronchoalveolar fluid. Because the histologic features were consistent with AMR, despite negative HLA antibodies, we tested for lung tissue–restricted nHAbs on serum collected on the day of transplantation, as previously described [2Bharat A. Kuo E. Saini D. et al.Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection.Ann Thorac Surg. 2010; 90 (discussion 1644): 1637-1644Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. The recipient showed positive responses for antibodies to collagen type V (214 μg/mL, normal <106 μg/mL), Kα1-tubulin (160.8 μg/ml, normal <145 μg/mL), and collagen type I (14 μg/mL, normal <7.3 μg/mL) but not nonlung antigens collagen types II and IV. The patient was treated with intravenous immunoglobulin (IVIG, 1 g/kg), rituximab (375 mg/m2), and bortezomib (1.3 mg/m2). Allograft function improved with resolution of infiltrates (Fig 1D) within 72-hours. Maintenance immunosuppression included tacrolimus (target trough level, 8 to 12 ng/mL), mycophenolate mofetil (1,000 mg twice daily), and prednisone (0.5 mg/kg). At 6 months, the forced expiratory volume in 1 second (FEV1) was 65% of predicted, and she remained breathing room air. Treatment with antibody-directed therapy for 6 months cleared the nHAbs.Fig 2Evidence supporting the diagnosis of antibody-mediated rejection in both recipients. (A) Immunoglobulin-G deposition (magnification 100×). (B) Complement deposition (magnification 40×).View Large Image Figure ViewerDownload (PPT) Recipient 2: The left lung was transplanted with the use of cardiopulmonary bypass support into a 66-year-old man with idiopathic pulmonary fibrosis, pulmonary hypertension, and left internal mammary artery bypass graft. The result of crossmatching was negative, and there were no HLA antibodies. After an uneventful recovery, he was discharged breathing room air on day 18 (Fig 1E). However, on day 24, he presented with hypoxemic respiratory failure and new allograft infiltrates (Fig 1F). Microbial cultures were negative, and an allograft biopsy specimen revealed AMR (Fig 1G) with IgG and C4D deposition (Fig 2A). The results of repeated crossmatching and PRA screening for HLA were negative. IgG-nHAbs against collagen types V and I and Kα1-tubulin were negative at transplantation. However, de novo antibodies to collagen type V (264 μg/mL), Kα1-tubulin (182.6 μg/mL), and collagen type I (19 μg/mL), but not collagen types II and IV, were identified on day 24. The patient received plasmapheresis, IVIG, and rituximab. Allograft function recovered in 72 hours, and at 6 months the chest roentgenogram was normal (Fig 1H); FEV1 was 78% of predicted. Lymphocytic crossmatching has significantly decreased HLA antibody–mediated hyperacute rejection after allotransplantation. Nevertheless, primary graft dysfunction (PGD) remains a frequent occurrence after lung transplantation [6Diamond J.M. Lee J.C. Kawut S.M. et al.Clinical risk factors for primary graft dysfunction after lung transplantation.Am J Respir Crit Care Med. 2013; 187: 527-534Crossref PubMed Scopus (417) Google Scholar]. In our series, recipient 2 had idiopathic pulmonary fibrosis and pulmonary hypertension, and he required cardiopulmonary bypass for transplantation, all risk factors for PGD [6Diamond J.M. Lee J.C. Kawut S.M. et al.Clinical risk factors for primary graft dysfunction after lung transplantation.Am J Respir Crit Care Med. 2013; 187: 527-534Crossref PubMed Scopus (417) Google Scholar]. Despite that, recipient 1 experienced PGD but not recipient 2. We have previously shown that preexisting nHAbs are present in about a third of lung recipients, and these can increase the risk of PGD sevenfold [7Bharat A. Saini D. Steward N. et al.Antibodies to self-antigens predispose to primary lung allograft dysfunction and chronic rejection.Ann Thorac Surg. 2010; 90: 1094-1101Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. The time course, histologic features, presence of preexisting nHAbs but not HLA antibodies, lack of other etiologic factors, and prompt improvement with antibody-mediated therapy are highly suggestive of nHAb-mediated hyperacute rejection that manifested as PGD in recipient 1. Therefore, it is possible that nHAb-mediated lung rejection is one possible cause of PGD. The native lung was unaffected, likely because sAgs remain sequestered, and therefore nHAbs cannot bind to the native lung. The development of de novo nHAbs in recipient 2 was possibly from memory B cells against sAgs resulting from the end-stage lung disease [8Stegall M.D. Raghavaiah S. Gloor J.M. The (re)emergence of B cells in organ transplantation.Curr Opin Organ Transplant. 2010; 15: 451-455Crossref PubMed Scopus (38) Google Scholar]. These memory B cells can form nHAbs upon reexposure to sAgs in the allograft after ischemia and reperfusion. Lung-restricted sAgs can be expressed for over a month after transplantation [9Yoshida 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: 724-735Crossref PubMed Scopus (152) Google Scholar], and the development of nHAbs during this time can cause AMR, as seen in recipient 2. Hence, we postulate that recipient 2 had AMR from de novo nHAbs. Our data suggest that antibodies against lung sAgs can lead to hyperacute or acute humoral rejection that can be treated upon early recognition. This is in agreement with recent murine studies [10Subramanian V. Ramachandran S. Banan B. et al.Immune response to tissue-restricted self-antigens induces airway inflammation and fibrosis following murine lung transplantation.Am J Transplant. 2014; 14: 2359-2366Crossref PubMed Scopus (50) Google Scholar]. Testing for these nHAbs should be considered during the workup for transplantation and in patients presenting with either unexplained PGD or posttransplantation AMR in the absence of HLA antibodies. Dr Bharat is supported by NHLBI K08 HL125940. T. Mohanakumar is supported by NIH HL 056643. Dr Chiu is supported by NIDDK T32 DK077662. The authors wish to thank Ms Elena Susan for administrative assistance in the preparation and submission of this manuscript." @default.
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• W2521101777 date "2016-10-01" @default.
• W2521101777 modified "2023-10-14" @default.
• W2521101777 title "Humoral Human Lung Allograft Rejection by Tissue-Restricted Non-HLA Antibodies" @default.
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