Early Donor Specific Antibodies After Lung Transplantation Lead to an Increase of CD56+CD16+ NK Cells in Peripheral Blood

Early Donor Specific Antibodies After Lung Transplantation Lead to an Increase of CD56+CD16+ NK Cells in Peripheral Blood

Abstracts S135 antero-lateral or clamshell incisions using intraoperative ECMO support. In 5 cases, we transplanted a right upper (RUL) + right middle...

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Abstracts S135 antero-lateral or clamshell incisions using intraoperative ECMO support. In 5 cases, we transplanted a right upper (RUL) + right middle lobe (RML) and a left upper lobe (LUL). The remaining patients received RUL and LUL (n= 2), RLL and LLL (n= 2 ), and complete right lung and LUL (n= 2). There were no postoperative air leaks requiring further intervention. The 30-day survival was 90.9%. Two patients died during the first year from graft failure (at day 11) and SIRS (at day 77), respectively. All other patients are still alive at 44.4±14.3 months. One patient developed BOS stage III and 7 recipients were hospitalized for infections at some point. All survivors are followed as outpatients and have little activity limitations. Their FVC and FEV1 is 52.2±20.2% and 51.6±18.8%, respectively. Conclusion: Although lobar lung transplantation has been used as a bailout strategy in cases of unexpected size mismatches or in very urgent patients, we show here that elective lobar lung transplantation can be performed safely with similar overall results as regular lung transplants. It is a valuable option for patients, mainly female with small thoraces. 3( 47) Early Donor Specific Antibodies After Lung Transplantation Lead to an Increase of CD56+CD16+ NK Cells in Peripheral Blood J. Salman ,1 F. Ius,1 A. Knoefel,1 W. Sommer,1 C. Kuehn,1 I. Tudorache,1 M. Avsar,1 J. Gottlieb,2 T. Welte,2 C. Falk,3 A. Haverich,1 G. Warnecke.1   1Department for Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; 2Department of Pneumology, Hannover Medical School, Hannover, Germany; 3Transplant Immunology, Institute of Transplant Immunology, Integrated Research and Treatment Center, Hannover Medical School, Hannover, Germany. Purpose: Natural killer (NK) cells play a key role in host defense due to their ability to release cytokines and to mediate cytolytic activity against tumor cells and virus-infected cells. The role of NK cells after lung transplantation (LTX) has not yet been thoroughly investigated. However, NK cells might be involved in immune recognition after kidney transplantation due to their capability to bind donor-specific anti-HLA-antibodies (DSA) by their Fcγ RIII (CD16). Therefore we hypothesized, that development of early DSA in lung transplant recipients leads to an upregulation of CD56+CD16+ NK Cells in peripheral blood. Methods: In 72 patients undergoing bilateral LTX, flow cytometry analysis of NK cells in peripheral blood according to their CD56 and CD16 expression was performed at 3 weeks after LTX and correlated to the existence of DSA within the first three weeks after LTX. Results: Mean age of the recipients was 49.6±13.0 yrs and 51.2% were male. Fifty-five patients (76.4%) developed DSA within the first three weeks after LTX. Three weeks after LTX, DSA+ patients showed a trend towards higher expression of CD56 dimCD16 + NK cells (88.9±2.0 vs 83.5±3.2%; p= 0 .08), whereas DSA- recipients revealed significantly lower expression of CD56brightCD16- NK cells (18.6±4.0 vs. 11.0±2.1%; p= 0.05). Conclusion: At 3 weeks after LTX, presence of DSA is associated with an increase of CD56+CD16+ NK cells, indicating an expansion of this cytotoxic NK subset. The significant reduction of the potentially regulatory CD56brightCD16- NK subset in DSA+ lung recipients suggests that this subset may act as an important counter regulator of the cytotoxic CD16+ NK subset.In order to further characterize the effect of DSA on the NK cell repertoire, mid to long term follow up is necessary also for a potential role of NK cells in development of chronic rejection (BOS) or immunological tolerance after Ltx. 3( 48) Predictors of Survival in Patients Diagnosed With Restrictive CLAD S.E. Verleden , D. Ruttens, E. Vandermeulen, H. Bellon, D.E. Van Raemdonck, B.M. Vanaudenaerde, G.M. Verleden, R. Vos.  Department of Clinical and Experimental Medicine, Laboratory of Pulmonology, Lung Transplant Unit, KU Leuven, Leuven, Belgium. Purpose: Chronic lung allograft dysfunction remains one of the main factors limiting long-term survival. Recent evidence demonstrated that besides bronchiolitis obliterans syndrome, other phenotypes of CLAD

exist, mostly with a restrictive pulmonary function. Those patients have been denominated as having restrictive CLAD and in general show poor survival. It is unknown which factors may predict survival at diagnosis of rCLAD. Methods: All patients diagnosed with rCLAD between 2007 and 08/2014 have been assessed in retrospect and parameters have been collected at the moment of diagnosis and the impact of the collected parameters has been assessed on survival using both unadjusted and adjusted analysis (SAS 9.1). Results: During the study period, 33 patients have been diagnosed with rCLAD with a median survival of 324 days. Unadjusted analysis showed that infiltrates in lower lobe or diffuse infiltrates (p= 0.0052), elevated CRP (p= 0.0012), acute onset (p= 0.0019), lymphocytic bronchiolitis on concomittant transbronchial biopsy (TBB) (p= 0.014), BAL eosinophils ≥ 2% (p= 0.0009) and elevated BAL neutrophils (p= 0.012) were associated with a worse survival after diagnosis, while native lung disease, gender, age at diagnosis, previous BOS, type of transplant, post-operative day of CLAD diagnosis, presence of anti-HLA antibodies, Aspergillus growth, CLAD stage at diagnosis, FVC/FVC best at diagnosis, acute rejection on concommitant TBB did not influence survival after diagnosis. Adjusted analysis showed that acute onset (p= 0.038), BAL eosinophils ≥ 2% (p= 0.020) and BAL neutrophilia (p= 0.033) were the determinants with the strongest association with survival after rCLAD diagnosis. Conclusion: This analysis demonstrates that BAL differential cell count and an acute onset of rCLAD were associated with a shorter survival time after rCLAD diagnosis. 3( 49) Peripheral Blood Gene Expression Identifies Damage-Associated Innate Immune Pathways in Patients With Primary Graft Dysfunction After Lung Transplantation E. Cantu ,1 J.M. Diamond,2 Y. Suzuki,1 J. Tiwari,1 B. Beduhn,1 J. Nellen,1 C. Borders,1 J. Ellis,1 D.J. Lederer,3 K. Meyer,4 R.J. Shah,2 N.J. Meyer,2 K. Milewski,1 J.W. Tobias,2 D.A. Baldwin,2 V.M. Van Deerlin,5 K.M. Olthoff,1 A. Shaked,1 J.D. Christie.2  1Surgery, University of Pennsylvania, Philadelphia, PA; 2Medicine, University of Pennsylvania, Philadelphia, PA; 3Medicine, Columbia University, New York, NY; 4Medicine, University of Wisconsin, Madison, WI; 5Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA. Purpose: Evidence from bronchial alveolar lavage gene expression suggests primary graft dysfunction (PGD) after lung transplantation is characterized by early inflammasome and innate immune pathway up-regulation in the lung. We sought to determine early systemic gene expression responses in recipient blood. Methods: Peripheral blood mononuclear cells were sampled from 102 lung transplant recipients within one hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study (CTOT-03). A custom panel of 100 hypothesis-driven mediators was measured using the Panomics platform. Gene expression data were normalized following the manufacturer’s protocol. Two outliers with clear expression cluster departure were excluded. We used a linear model to test the differences in the expression after transplant between the patients with and without PGD, adjusting for age. To avoid inflated false positive rates due to multiple statistical comparisons, we used the Benjamini-Hochberg false discovery rate approach and reported the adjusted p-values. Results: 100 samples were analyzed. Genes with skewed distributions were log-transformed before the analysis. 24 gene products met the FDR significance cutoff for PGD association (Table). Among the top 3 most significantly dysregulated genes were FASLG, CD27 and PTX3 important in cell apoptosis, T cell and innate immunity (0.0036, 0.0105, and 0.0107, respectively). GATHER analysis of significantly associated genes highlighted 4 pathways (Cytokine-cytokine receptor interaction; Jak-STAT signaling; Toll-like receptor signaling and Apoptosis) with significant dysregulation. Conclusion: In the early phases of PGD in the lung, dysregulation of inflammasome and innate immune pathways is evident in circulating mononuclear cells suggesting effects are not just a local phenomenon. The Toll-like receptor pathway may be critical to both local and systemic responses in clinical PGD.