Elevation of Antidonor Immunoglobulin M Levels Precedes Acute Lung Transplant Rejection

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1 Elevation of Antidonor Immunoglobulin M Levels Precedes Acute Lung Transplant Rejection Kentaroh Miyoshi, MD, Yoshifumi Sano, MD, Masaomi Yamane, MD, Shinichi Toyooka, MD, Takahiro Oto, MD, and Shinichiro Miyoshi, MD Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan GENERAL THORACIC Background. No useful noninvasive biomarker exists for diagnosing acute rejection after lung transplantation (LTx). In this study, antidonor T-cell antibodies were monitored daily in living-donor lobar LTx recipients to determine whether they are correlated with the onset of steroid-responsive typical acute rejection. Methods. Ten nonsensitized patients who underwent bilateral living-donor lobar LTxs donated from 2 persons were analyzed. In 5 patients, unilateral acute rejection developed during the first 14 days after LTx and responded to subsequent pulse steroid therapies. The other patients experienced no rejection episodes during the period. Immunoreactivity against T cells from each lobe of the donors was monitored daily by detecting antidonor immunoglobulin (Ig) M and IgG using flow cytometry crossmatching for 14 days after LTx. Results. There was a remarkable increase in IgM levels against rejected grafts around the onset of acute rejection, but this increase was not observed against nonrejected grafts. The mean IgM levels against rejected grafts 14 days after transplantation was significantly higher than that against nonrejected grafts in the acute rejection group (p 0.009) and the no rejection group (p 0.010). In the acute rejection group, the IgM level against rejected grafts became significantly higher than those against nonrejected grafts 2 days before the clinical onset of acute rejection. These trends were statistically marginal or not detected for IgG levels. Conclusions. Significant immunoreactivity of IgM, but not IgG, preceded the clinical onset of acute rejection. Antidonor IgM monitoring can contribute to the early detection of steroid-responsive acute rejection. (Ann Thorac Surg 2011;92:1233 8) 2011 by The Society of Thoracic Surgeons Acute rejection is a common complication after lung transplantation (LTx) and is the most important independent risk factor for chronic allograft failure [1, 2]. Timely diagnosis of acute rejection is sometimes difficult in the early posttransplant period because its clinical manifestation is likely to be complicated by other inflammatory pathologies, such as ischemia-reperfusion injury and infection. No effective noninvasive biomarker for predicting acute rejection is currently in use for clinical LTx, and invasive lung biopsy after clinical onset is the gold standard for definitive diagnosis of acute rejection. After solid-organ transplantation, immunologic reactions that are activated by interactions between helper T cells and B cells can promote de novo donor-specific alloantibody (donor-specific alloantibody) production, which has recently been emphasized as one of the risk factors for chronic allograft failure [3 9]. According to a study of a large-scale series of kidney transplantations, acute rejection episodes were significantly associated with the development of de novo donor-specific alloantibody after transplantation [10]. Generally, cellular immunity through the Accepted for publication April 26, Address correspondence to Dr Kentaroh Miyoshi, Department of Cancer and Thoracic Surgery, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama , Japan; kentarohmiyoshi@yahoo.co.jp. CD4 Th1 pathway is considered to play a major role in acute rejection, and the details of the humoral immune response during acute cellular rejection are not well known. However, cellular immunity induced by CD4 Th2 cells can prompt specific B cells to produce antidonor antibodies during acute rejection [11]. The Th1 and Th2 cells mutually inhibit each other s activity through cytokine signals but can coexist. We previously reported the early elevation of circulating immunoglobulin (Ig) M levels against donor lymphocytes in histologically proven acute cellular rejection in rat allo-ltx models [12, 13]. Those studies suggested that a dynamic humoral immune response occurs even in cellular rejection. In addition, some recent research of kidney transplantation has provided increasing evidence that B and plasma cells infiltrate the allograft during acute cellular rejection, which supports the postulate that humoral immunity is activated in cellular rejection [14 16]. In the present study, we investigated daily antidonor T-cell antibody (IgM and IgG) levels by means of a flow cytometry crossmatch technique in the early phase after bilateral living-donor lobar LTx with donation from 2 donors. The purpose of this study was to examine the daily levels of antidonor antibodies in patients with and without steroid-responsive acute rejection and to elucidate whether monitoring the humoral response can contribute to the early detection of typical acute rejection in clinical settings by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 1234 MIYOSHI ET AL Ann Thorac Surg ANTIDONOR IGM AND ACUTE REJECTION 2011;92: Patients and Methods Patient Characteristics From October 1998 to November 2009, bilateral living donor lobar LTx was performed at Okayama University Hospital in 50 patients with end-stage pulmonary disease. Of 32 patients with no previous sensitization (eg, blood transfusion and multiparity), 5 patients who had unilateral acute rejection (AR) during the first 14 days after LTx (AR group; patients 1 through 5) and 5 patients who had no episodes of acute rejection in either of the transplanted lobes during the same period (no rejection [NR] group; patients 6 through 10) were retrospectively analyzed. Eighteen patients with presensitization or complement-dependent cytotoxicity and 22 patients with bilateral or multiple acute rejection during the first 14 days after LTx were excluded from this study. The patient characteristics of each group are shown in Table 1. All patients underwent LTx in which right and left lower lobes were removed from 2 donors (relatives or spouses) and implanted into the recipient. The donors had completely compatible ABO blood types. The patients received adequate immunosuppressive treatment with a triple-drug combination regimen that consisted of cyclosporine/tacrolimus plus azathioprine/mycophenolate mofetil plus prednisone. The Institutional Review Board of Okayama University Hospital approved this study, and written informed consent was obtained from all the patients and their donors for examining their blood samples. Flow Cytometry Crossmatching Peripheral blood samples were collected from recipients before LTx and daily for the first 14 days after LTx. The IgM and IgG levels in the sera of recipient against T cells from each side of the donors were analyzed retrospectively using flow cytometry crossmatching (Fig 1). The levels of antidonor T-cell antibodies in the recipients were monitored for a total of 20 grafts (donors) during the first 14 days after LTx. Donor lymphocytes were isolated from 20 to 50 ml of peripheral blood by Ficoll-amidotrizoate centrifugation and cryopreserved at 80 C in 10% dimethyl sulfoxide. A total of to donor lymphocytes were incubated with 20 L of the daily sampled recipient sera for 30 minutes. Crossmatched cells were resuspended in 10 L of FITC-conjugated F(ab=) 2 rat anti-human IgM or IgG heavy chain-specific antibody (BD Biosciences Pharmingen, San Jose, CA). Additionally, 5 L each of CyChrome-conjugated anti-cd3 monoclonal antibody and phycoerythrinconjugated anti-cd20 monoclonal antibody (BD Biosciences Pharmingen) were mixed to separate T cells from B cells. Flow cytometry with three-color fluorescence was performed using a FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ). CellQuest software (Becton Dickinson) was used for data processing. From each sample, 10,000 cells were captured in the lymphocyte gate. The T cells were selected by positive gating only with Cy- Chrome-conjugated anti-cd3. The IgM and IgG fluorescence data were processed into mean channel fluorescence. The pretransplant mean channel fluorescence value for each patient was defined as the control value, and the levels of de novo antibodies (IgM and IgG) for each posttransplant day were presented as fold induction over the pretransplant value. In a preliminary experiment, preoperative IgM and IgG values in the objective recipient serum were confirmed to be comparable to those in the healthy, nontransfused male sera. Diagnosis and Treatment of Acute Rejection Unilateral acute rejection was diagnosed cautiously by experienced clinicians based on the following clinical findings: (1) elevation of an inflammatory marker (C-reactive protein); (2) deteriorated oxygenation; (3) unilateral peribronchovascular infiltration detected by chest roentgenography or computed tomography; (4) increased serous airway secretion from unilateral graft detected by daily bronchoscopy; and (5) increased unilateral serous pleural effusion. The clinical onset of acute rejection was marked by the day when all of the above signs were detected. Transbronchial lung biopsy was not performed after living-donor lobar LTx because recipients with a small volume of transplanted lungs are likely to develop massive bleeding and pneumothorax, which can easily become critical. Acute rejection in the AR group was treated with pulse steroid Table 1. Patient Demographics Patient No. Age at LTx, Years Sex Diagnosis Immunosuppressants Acute Rejection 1 53 Female IPF CSA AZ P 2 27 Female IPAH FK MMF P 3 28 Female IPAH CSA AZ P 4 44 Female IPF CSA AZ P 5 11 Male IPAH CSA AZ P 6 19 Female IPAH FK MMF P 7 38 Female IPF CSA AZ P 8 45 Female BO CSA AZ P 9 49 Female BO CSA AZ P Male IPAH FK MMF P AZ azathioprine; BO bronchiolitis obliterans; CSA cyclosporine; FK tacrolimus; IPAH idiopathic pulmonary arterial hypertension; IPF idiopathic pulmonary fibrosis; LTx lung transplantation; MMF mycophenolate mofetil; P prednisone.

3 Ann Thorac Surg MIYOSHI ET AL 2011;92: ANTIDONOR IGM AND ACUTE REJECTION 1235 Fig 1. Outline of the study. Donor lymphocytes were isolated from peripheral blood and incubated with recipient sera. Both immunoglobulin (Ig)M and IgG levels in recipient sera against T cells from both donor grafts were analyzed daily using flow cytometry crossmatching through the first 14 days after transplantation. Each recipient received a graft from 2 donors, and therefore, antibody monitoring of 10 recipients was performed for a total of 20 donors. The development of acute rejection in the acute rejection (AR) group is unilateral. Accordingly, we obtained data associated with acute rejection for 5 recipients. (Lt. D left donor; LTx lung transplantation; POD postoperative day; NR no rejection; R recipient; Rt. D right donor.) GENERAL THORACIC treatment of 500 mg/day methylprednisolone for 3 days, which was started on the day of clinical onset. Statistical Analysis Two-category comparisons were performed by Mann- Whitney s U test for quantitative data. Differences were considered as clinically significant at p less than Calculations and statistical tests were performed using SPSS 11.0J statistical software (SPSS, Chicago, IL). Results Daily Measurements of Antidonor T-Cell Antibody Levels After LTx Changes in the de novo IgM/IgG levels against each graft in each recipient are shown in Figure 2. In the AR group, the patients had acute rejection on postoperative days 5 to 10. The IgM levels against the rejected graft in 4 of the 5 with acute rejection were shown to peak on the day of clinical Fig 2. Overview of the 14-day monitoring results for (A) acute rejection group and (B) no rejection group. In each line chart, both anti-right graft antibody levels (solid line) and anti-left graft antibody levels (dashed line) are shown for each recipient. Antidonor T-cell antibody values for each posttransplant day are presented as the fold induction over the pretransplant mean channel fluorescence value. Unilateral acute rejection developed on the day indicated by the triangles. (Ig immunoglobulin; POD postoperative day; Pt patient.)

4 GENERAL THORACIC 1236 MIYOSHI ET AL Ann Thorac Surg ANTIDONOR IGM AND ACUTE REJECTION 2011;92: Fig 3. Mean de novo antidonor T-cell (A) immunoglobulin (Ig)M levels and (B) IgG levels during the 14 days after transplantation (PostTx) for the rejected grafts in the acute rejection (AR) group (n 5), nonrejected grafts in the AR group (n 5), and grafts in the no rejection (NR) group (n 10). Data were plotted for each of the 20 donors. The IgM levels against the rejected grafts were significantly higher than those against the nonrejected grafts in the AR group (p 0.009) and the grafts in the NR group (p 0.010). A similar, but marginally significant at best, trend was observed for mean IgG values. (Ab antibody.) onset of acute rejection. However, even in the patient without a spike in IgM levels (patient no. 4), the levels of anti-left (rejected) graft antibody increased by approximately twofold around the onset of acute rejection. Regarding IgG, the peak level against the rejected graft was markedly increased 2 or 3 days after onset of acute rejection in 3 patients. The IgG levels against the rejected grafts in the other 2 patients with acute rejection remained stable. All of the patients in the AR group clinically responded to the steroid pulse therapy, and IgM levels against the rejected grafts declined after therapy was initiated. Regarding the antidonor antibody levels against nonrejected grafts in the AR group and all grafts in the NR group, neither IgM nor IgG level increased sharply after transplantation. There was no clear correlation between the elevation of antibody levels and the combination of immunosuppressant drugs. In Figure 3, mean de novo IgM and IgG levels during the 14 days after transplantation are compared among those against rejected grafts in the AR group (n 5), nonrejected grafts in the AR group (n 5), and grafts in the NR group (n 10). The mean IgM levels against the rejected grafts were significantly higher than those against the nonrejected grafts in the AR group (p 0.009) and the grafts in NR group (p 0.010). The mean IgG levels against the rejected grafts also tended to be higher than those against nonrejected grafts, but the trend was at best marginally significant (p 0.047, 0.085). Only IgM levels against the rejected grafts increased remarkably during acute rejection episodes, and donor-specific alloantibody levels against the nonrejected grafts in the AR group or against all grafts in the NR group did not greatly change after LTx. De Novo Antidonor T-Cell Antibody Levels Around Time of Acute Rejection in AR Group The levels of IgM/IgG against the rejected/nonrejected grafts between 3 days before and 3 days after the clinical onset of acute rejection (from day 3 today 3, day 0 being the day of rejection) are shown in Figure 4. Fold changes in the IgM levels of the 5 patients for the rejected/nonrejected grafts (mean SD) were as follows: / on day 3, / on day 2, / on day 1, / on day 0, / on day 1, Fig 4. The serum levels of de novo antidonor T-cell antibodies, (A) immunoglobulin (Ig)M levels and (B) IgG, around the acute rejection episode in the acute rejection (AR) group (n 5). The antibody values for rejected grafts (solid bars) are compared with those for nonrejected grafts (open bars) in the AR group during the same period (day 3 today 3 relative to the onset of acute rejection). The IgM levels against the rejected grafts became significantly higher (asterisks) than those against nonrejected grafts 2 days before the onset of acute rejection. No remarkable increase in IgG levels against the rejected grafts was observed before acute rejection.

5 Ann Thorac Surg MIYOSHI ET AL 2011;92: ANTIDONOR IGM AND ACUTE REJECTION / on day 2, and / at day 3. Fold changes in IgG levels for the rejected/nonrejected grafts (mean SD) in the same patients over the same period were as follows: / on day 3, / on day 2, / at day 1, / on day 0, / on day 1, / on day 2, and / on day 3. The IgM levels against the rejected grafts were significantly higher than those against the nonrejected grafts from day 2 today 3 (p 0.05). There was no statistically significant increase in the IgG levels against the rejected grafts before acute rejection. Although increasing IgG levels were observed in some patients after LTx, the IgG data for rejected grafts varied widely throughout the period. Comment 1237 This retrospective study indicated that increases in the de novo antidonor T-cell IgM levels in the sera of recipients precedes the clinical onset of acute rejection after clinical LTx. The patients in this study underwent LTx from 2 donors concurrently, enabling us to compare the levels of antibodies against the rejected graft and the nonrejected graft in identical conditions (in the same recipient). We excluded multiple/bilateral rejection cases to simplify the analysis and focused on the comparison between single rejection and nonrejection cases. The patients with acute rejection exhibited significantly higher levels of serum IgM against the T cells of the rejected graft than against the nonrejected graft beginning 2 days before acute rejection. In contrast, the patients in the NR group exhibited much less fluctuation in antibody levels against either graft during the 14 days after LTx. The results suggest that the elevation of IgM levels against donor antigens can predict the onset of acute rejection. Only a few studies of antidonor IgM levels have been conducted thus far because IgM has been generally considered nonfunctional in graft injuries after transplantation. This study highlights the role of antidonor IgM antibodies, which has been rarely discussed in organ transplantation. We intended to evaluate sensitive changes in the humoral response associated with typical steroid-responsive acute cellular rejection. The detected antibodies did not appear functional, at least in the acute phase, because all patients responded well to pulse steroid therapy. Donorspecific alloantibodies were reportedly detected even without the pathologic or clinical finding of humoral rejection [6, 17]. Although this phenomenon still remains poorly understood, such a humoral response may represent the potential immunoreactivity against the graft, including the strength of cellular response. These latent antibodies directed against donor antigens are the biomarkers that we targeted in this study. In particular, IgM responses are sensitive to immunoreactivity because primitive alloresponses would easily allow a mild B-cell response to produce IgM even without a cognate interaction with CD4 T cells [11]. As a result, IgM responses can be observed more frequently in acute rejection, and monitoring serum antidonor IgM levels is considered helpful in predicting acute rejection. There was also a report suggesting a correlation between IgM responses and acute rejection after kidney and heart transplantation, which could support our results for LTx [18]. According to our results, IgG monitoring appeared ineffective for diagnosing acute rejection. Unlike the IgM data, no statistically significant increase in IgG levels was observed around the time of acute rejection. Although 3 of 5 patients with acute rejection were revealed to have a surge in their donor-specific IgG levels, the levels of donor-specific IgG for other 2 patients remained steady throughout the episode of acute rejection. This result appears consistent with reports by other researchers describing humoral immune responses associated with acute cellular rejection in renal transplantation and LTx [19 21]. They indicated that only approximately 10% to 30% of patients with acute cellular rejection were considered to experience a positive conversion of donor-specific IgG after transplantation [4, 19, 21]. Production of IgG is achieved by the B-cell class switch, which requires strong cognate interactions between the CD4 and B cells of recipients mainly through an indirect pathway [11]. Therefore, under immunosuppressive treatment, some recipients, but not all, experience a positive conversion of antidonor IgG after LTx. In addition, there was no remarkable fluctuation in the anti B-cell antibody levels in this investigation (data not shown), indicating that monitoring their levels is not useful for predicting acute rejection. One of the reasons why the response to B cells was equivocal in the early phase of LTx might be that the expression of class II antigen is generally much lower than that of class I antigen on the allograft. In fact, our fundamental study using a rat allotransplant model revealed no significant response of antibodies against donor B cells under immunosuppression in the early phase of LTx [13]. Furthermore, some other previous reports of kidney transplantation also support the results in which the anti class II response was less frequently observed than the anti class I response after transplant [3]. Overall, we consider that only antidonor T-cell IgM levels are helpful for diagnosing or predicting acute rejection. Transbronchial lung biopsy through bronchoscopy is currently considered the preferred procedure for the definitive diagnosis of acute rejection. The Lung Rejection Study Group has recommended biopsy of five pieces of alveolated lung parenchyma for adequate diagnostic sensitivity. Although the procedure generally is considered safe, some complications such as hypoxia, bleeding, and pneumothorax have been reported [22, 23]. This procedure is occasionally critical for the transplant recipient, especially if they receive a small graft (eg, lobe or single lung). Meanwhile, there are several benefits of our antibody monitoring method. First, this serum examination is a much simpler and less invasive procedure that requires only a few hours to produce test results. It can also monitor immunologic activity even in asymptomatic recipients. Methods such as those presented in this study can contribute to the diagnosis of acute rejection in posttransplant patients who are too critically ill to undergo multiple biopsies. Second, acute GENERAL THORACIC

6 GENERAL THORACIC 1238 MIYOSHI ET AL Ann Thorac Surg ANTIDONOR IGM AND ACUTE REJECTION 2011;92: rejection could be detected at an early stage so that subsequent inflammation would be prevented before its severe activation by introducing an intensive immunosuppressive management. Consequently, the risk of bronchiolitis obliterans syndrome could be also reduced. Our distinctive study objects (development of unilateral acute rejection in bilateral living-donor lobar LTx recipients) are ideal to compare the immunoreactivity against the rejected graft to that against the nonrejected graft, but there may be several limitations in this study. First, lung biopsy to histologically confirm acute rejection was not performed. Therefore, other possible steroid-responsive pulmonary pathologies could not be entirely excluded. Second, cellbased testing may not be completely specific to donors human leukocyte antigen because there are some possible confounding effects of other antigens present on the cell surface. Therefore, we stress that we examined antibodies to whole self-antigens in this study. In particular, IgM is widely believed to be an autoantibody. More detailed evaluation about antibody specificity by using a solid-phase technique is needed to conclude that the detected antibodies were truly donor-specific. However, our results, demonstrating the steroid-responsive clinical course and remarkably heterogeneous humoral responses to two grafts in the same recipient, strongly supported our postulation that acute rejection usually affects the humoral response only to the rejected graft. Finally, this study did not directly provide a concrete methodology to manage LTx recipients who received a donation from a single deceased donor. Further investigations are crucial before IgM monitoring can be applied in clinical practice for these typical patients. Intensive investigation of antidonor IgM data in both the stable condition and during acute rejection should be conducted to determine the cutoff values and diagnostic criteria. In conclusion, antidonor T-cell IgM levels were significantly elevated beginning 2 days before the clinical onset of steroid-responsive acute rejection. Monitoring the latent humoral response can contribute to the early detection of acute rejection after LTx. Large-scale clinical studies are warranted for the clinical application of this method to LTx recipients. This study was supported by a grant from the Japan Society for the Promotion of Science. References 1. Stewart KC, Patterson GA. Current trends in lung transplantation. Am J Transplant 2001;1: Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002;21: Piazza A, Poggi E, Borrelli L, et al. Impact of donor-specific antibodies on chronic rejection occurrence and graft loss in renal transplantation: posttransplant analysis using flow cytometric techniques. Transplantation 2001;71: Palmer SM, Davis RD, 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: Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLAspecific antibodies as a predictor of renal transplant outcome. Transplantation 2003;75: Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant 2004;4: Girnita AL, Duqesnoy R, Yousem SA, et al. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant 2005;5: Oliveira JG, Monteiro MS, Teixeira JF, et al. Humoral immune response after kidney transplantation is enhanced by acute rejection and urological obstruction and is downregulated by mycophenolate mofetil treatment. Transpl Int 2005;18: Mao Q, Terasaki PI, Cai J, et al. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant 2007;7: Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donorspecific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol 2005;16: Steele DJ, Laufer TM, Smiley ST, et al. Two levels of help for B cell alloantibody production. J Exp Med 1996;183: Yamane M, Sano Y, Nagahiro I, et al. Humoral immune responses during acute rejection in rat lung transplantation. Transpl Immunol 2003;11: Yamane M, Sano Y, Shimizu N. Significant changes in the alloantibody after lung transplantation in the cyclosporine treated rat model. Transpl Immunol 2004;12: Charney DA, Nadasdy T, Lo AW, Racusen LC. Plasma cell-rich acute renal allograft rejection. Transplantation 1999; 68: Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 2003;349: Hippen BE, DeMattos A, Cook WJ, Kew CE, Gaston RS. Association of CD20 infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant 2005;5: Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc 2009;6: Stastny P, Ring S, Lu C, Arenas J, Han M, Lavingia B. Role of immunoglobulin (Ig) -G and IgM antibodies against donor human leukocyte antigens in organ transplant recipients. Hum Immunol 2009;70: Girnita AL, McCurry KR, Iacono AT, et al. HLA-specific antibodies are associated with high-grade and persistentrecurrent lung allograft acute rejection. J Heart Lung Transplant 2004;23: Snyder LD, Palmer SM. Immune mechanisms of lung allograft rejection. Semin Respir Crit Care Med 2006;27: Everly MJ, Everly JJ, Arend LJ, et al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 2009;9: Hopkins PM, Aboyoun CL, Chhajed PN, et al. Prospective analysis of 1235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 2002;21: Chan CC, Abi-Saleh WJ, Arroliga AC, et al. Diagnostic yield and therapeutic impact of flexible bronchoscopy in lung transplant recipients. J Heart Lung Transplant 1996;15:

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