The Autoimmune-Associated Single Nucleotide Polymorphism Within PTPN22 Correlates With Clinical Outcome After Lung Transplantation

Obstructive chronic lung allograft dysfunction (BOS) is the major limiting factor for lung transplantation (LTx) outcome. PTPN22 is described as the hallmark autoimmunity gene, and one specific single nucleotide polymorphism (SNP), rs2476601, is associated with multiple autoimmune diseases, impaired T cell regulation, and autoantibody formation. Taking into consideration the contribution of autoimmunity to LTx outcome, we hypothesized that polymorphisms in the PTPN22 gene could be associated with BOS incidence. We selected six SNPs within PTPN22 and analyzed both patient and donor genotypes on BOS development post-LTx. A total of 144 patients and matched donors were included, and individual SNPs and haplotype configurations were analyzed. We found a significant association between patients carrying the heterozygous configuration of rs2476601 and a higher risk for BOS development (p = 0.005, OR: 4.400, 95%CI: 1.563–12.390). Kaplan-Meier analysis showed that heterozygous patients exhibit a lower BOS-free survival compared to patients homozygous for rs2476601 (p = 0.0047). One haplotype, which solely contained the heterozygous risk variant, was associated with BOS development (p = 0.015, OR: 7.029, 95%CI: 1.352–36.543). Our results show that LTx patients heterozygous for rs2476601 are more susceptible for BOS development and indicate a deleterious effect of the autoimmune-related risk factor of PTPN22 in patients on LTx outcome

Long-term follow up of humoral immune status in adult lung transplant recipients

BACKGROUND: Lung transplant recipients have an increased risk for infections in the posttransplant period due to immunosuppressive therapy. Protection against infections can be achieved through vaccination, but the optimal vaccination schedule in lung transplant recipients is unknown. Data on long-term immunological follow up and vaccination responses after lung transplantation are scarce. METHODS: Here we present long-term immunological follow up of a cohort of 55 lung transplant recipients. This includes detailed antibody responses after 23-valent pneumococcal polysaccharide vaccination (23vPPV). RESULTS: All patients were vaccinated with 23vPPV prior to transplantation. Median follow-up after transplantation was 6.6 years (379 patient-years). Following transplantation, there is a significant decrease of all immunoglobulins, IgG subclasses and pneumococcal polysaccharide antibodies. After the first year posttransplantation there is a gradual increase of all immunoglobulins and IgG subclasses, but values were always significantly lower than in the pretransplant period. After a median of 4.4 years posttransplantation patients were revaccinated with 23vPPV. The pneumococcal polysaccharide antibody response was impaired in 87% of patients (ie, antibody titer above cutoff and 2-fold increase between pre and postvaccination values for <70% of serotypes). CONCLUSION: We found that impairment of humoral immunity was most outspoken in the first year after lung transplantation. Immunoglobulin levels remain decreased several years after transplantation and the response to pneumococcal polysaccharide vaccine was significantly lower posttransplantation compared to the pretransplantation response. However, most patients did show a partial response to vaccination. Based on our results, revaccination with pneumococcal vaccines after transplantation should be considered 1 year after transplantation

Antibodies against apoptotic cells present in end-stage lung disease patients do not correlate with clinical outcome after lung transplantation

Antibodies against HLA and non-HLA are associated with transplantation outcome. Recently, pretransplant serum IgG antibody levels against apoptotic cells were found to correlate with kidney allograft loss. We investigated the presence of these antibodies in lung transplantation (LTx) patients and evaluated the correlation of pre-LTx serum levels of IgG antibodies against apoptotic cells with LTx outcome. These cells included donor lung endothelial cells (ECs) obtained from lung perfusion fluid collected during LTx procedure. Cells were isolated, expanded in vitro, and analyzed as targets for antiapoptotic cell reactivity. Cultured cells exhibited EC morphology and were CD31+, CD13+, and vWF+. End-stage lung disease patients showed elevated serum IgG levels against apoptotic lung EC (p = 0.0018) compared to healthy controls. Interestingly, the levels of circulating antibodies directed against either apoptotic Jurkat cells or apoptotic lung ECs did not correlate, suggesting a target cell specificity. We observed no correlation between chronic or acute rejection and pre-LTx serum levels of antiapoptotic antibodies. Also, these levels did not differ between matched patients developing chronic rejection or not during follow-up or at the time of diagnosis, as they remained as high as prior to transplantation. Thus, circulating levels of antiapoptotic cell antibodies are elevated in end-stage lung disease patients, but our data do not correlate with outcome after LTx

Association between a Single Donor TARC/CCL17 Promotor Polymorphism and Obstructive Chronic Lung Allograft Dysfunction after Lung Transplantation

Lung transplantation (LTx) outcome is hampered by development of chronic rejection, often manifested as the bronchiolitis obliterans syndrome (BOS). Low serum levels of thymus and activation-regulated chemokine (TARC/CCL17), a chemoattractant, measured during the first month post-LTx are predictive for BOS development. Since TARC/CCL17 promotor polymorphisms correlate with serum TARC/CCL17 levels, we investigated seven single-nucleotide polymorphisms (SNPs) within this region and their potential association with LTx outcome. We analyzed donor and patient SNP configurations and haplotypes and observed a trend between a donor SNP (rs223899) configuration and patient TARC/CCL17 serum levels post-LTx (p = 0.066). Interestingly, this SNP configuration in patients did not show any correlation with pre-LTx TARC/CCL17 serum levels (p = 0.776). Survival analysis showed that receiving a graft from a donor heterozygous for rs223899 has a disadvantageous impact on transplantation outcome. When stratified per donor SNP genotype, patients receiving a transplant from a heterozygous donor showed a lower BOS-free survival (p = 0.023) and survival rate (p = 0.0079). Since rs223899 is located within a NFκB binding site, heterozygosity at this position could result in a reduced TARC/CCL17 expression. Our data indicate that a single TARC/CCL17 promotor SNP in the donor correlates with lower serum TARC/CCL17 levels measured 1 month after LTx and affects clinical outcome after LTx

Association between a Single Donor TARC/CCL17 Promotor Polymorphism and Obstructive Chronic Lung Allograft Dysfunction after Lung Transplantation

Lung transplantation (LTx) outcome is hampered by development of chronic rejection, often manifested as the bronchiolitis obliterans syndrome (BOS). Low serum levels of thymus and activation-regulated chemokine (TARC/CCL17), a chemoattractant, measured during the first month post-LTx are predictive for BOS development. Since TARC/CCL17 promotor polymorphisms correlate with serum TARC/CCL17 levels, we investigated seven single-nucleotide polymorphisms (SNPs) within this region and their potential association with LTx outcome. We analyzed donor and patient SNP configurations and haplotypes and observed a trend between a donor SNP (rs223899) configuration and patient TARC/CCL17 serum levels post-LTx (p = 0.066). Interestingly, this SNP configuration in patients did not show any correlation with pre-LTx TARC/CCL17 serum levels (p = 0.776). Survival analysis showed that receiving a graft from a donor heterozygous for rs223899 has a disadvantageous impact on transplantation outcome. When stratified per donor SNP genotype, patients receiving a transplant from a heterozygous donor showed a lower BOS-free survival (p = 0.023) and survival rate (p = 0.0079). Since rs223899 is located within a NFκB binding site, heterozygosity at this position could result in a reduced TARC/CCL17 expression. Our data indicate that a single TARC/CCL17 promotor SNP in the donor correlates with lower serum TARC/CCL17 levels measured 1 month after LTx and affects clinical outcome after LTx

Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction after Lung Transplantation

CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung diseases, however overall survival is hampered by chronic lung allograft dysfunction development, which presents itself obstructively as the bronchiolitis obliterans syndrome (BOS). We hypothesized that, due to cellular damage and activation during chronic inflammation, sCD59 serum levels can be used as biomarker preceding BOS development. We analyzed sCD59 serum concentrations in 90 LTx patients, of whom 20 developed BOS. We observed that BOS patients exhibited higher sCD59 serum concentrations at the time of diagnosis compared to clinically matched non-BOS patients (p = 0.018). Furthermore, sCD59 titers were elevated at 6 months post-LTx (p = 0.0020), when patients had no BOS-related symptoms. Survival-analysis showed that LTx patients with sCD59 titers ≥400 pg/ml 6 months post-LTx have a significant (p <0.0001) lower chance of BOS-free survival than patients with titers ≤400 pg/ml, 32% vs. 80% respectively, which was confirmed by multivariate analysis (hazard ratio 6.2, p <0.0001). We propose that circulating sCD59 levels constitute a novel biomarker to identify patients at risk for BOS following LTx

The autoimmune-associated single nucleotide polymorphism within PTPN22 correlates with clinical outcome after lung transplantation

Obstructive chronic lung allograft dysfunction (BOS) is the major limiting factor for lung transplantation (LTx) outcome. PTPN22 is described as the hallmark autoimmunity gene, and one specific single nucleotide polymorphism (SNP), rs2476601, is associated with multiple autoimmune diseases, impaired T cell regulation, and autoantibody formation. Taking into consideration the contribution of autoimmunity to LTx outcome, we hypothesized that polymorphisms in the PTPN22 gene could be associated with BOS incidence. We selected six SNPs within PTPN22 and analyzed both patient and donor genotypes on BOS development post-LTx. A total of 144 patients and matched donors were included, and individual SNPs and haplotype configurations were analyzed. We found a significant association between patients carrying the heterozygous configuration of rs2476601 and a higher risk for BOS development (p = 0.005, OR: 4.400, 95%CI: 1.563-12.390). Kaplan-Meier analysis showed that heterozygous patients exhibit a lower BOS- free survival compared to patients homozygous for rs2476601 (p = 0.0047). One haplotype, which solely contained the heterozygous risk variant, was associated with BOS development (p = 0.015, OR: 7.029, 95%CI: 1.352-36.543). Our results show that LTx patients heterozygous for rs2476601 are more susceptible for BOS development and indicate a deleterious effect of the autoimmune-related risk factor of PTPN22 in patients on LTx outcome

Accuracy of CT Pulmonary Artery Diameter for Pulmonary Hypertension in End-Stage COPD

INTRODUCTION: Pulmonary hypertension (PH) in COPD is associated with a higher mortality and an increased risk on exacerbations compared to COPD patients without PH. The aim was to evaluate the diagnostic value of pulmonary artery (PA) measurements on chest computed tomography (CT) for PH in end-stage COPD. METHODS: COPD patients evaluated for eligibility for lung transplantation between 2004 and 2015 were retrospectively analyzed. Clinical characteristics, chest CTs, spirometry, and right-sided heart catheterizations (RHC) were studied. Diameters of PA and ascending aorta (A) were measured on CT. Diagnostic properties of different cut-offs of PA diameter and PA:A ratio in diagnosing PH were calculated. RESULTS: Of 92 included COPD patients, 30 (32.6 %) had PH at RHC (meanPAP > 25 mm Hg). PA:A > 1 had a negative predictive value (NPV) of 77.9 % and a positive predictive value (PPV) of 63.1 % with an odds ratio (OR (CI 95 %)) of 5.60 (2.00-15.63). PA diameter ≥30 mm had a NPV of 78 % and PPV of 64 % with an OR (CI 95 %) of 6.95 (2.51-19.24). CONCLUSION: A small PA diameter and PA:A make the presence of PH unlikely but cannot exclude its presence in end-stage COPD. A large PA diameter and PA:A maybe used to detect PH early