Acute Rejection In Lung Transplantation Research Articles

Efficacy of surveillance bronchoscopy versus clinically indicated bronchoscopy for detection of acute lung transplant rejection: a systematic review and meta-analysis.

Acute allograft rejection after lung transplantation significantly increases the risk of developing bronchiolitis obliterans syndrome, a form of chronic lung allograft dysfunction and the leading cause of mortality beyond the initial post-transplantation year. There are two diagnostic approaches available for monitoring lung transplant recipients: clinically indicated bronchoscopy (CIB) and surveillance bronchoscopy (SB). The efficacy of both methods and their relative superiority in detecting acute rejection have not been conclusively determined. We systematically searched the MEDLINE, Embase, Cochrane and Scopus databases from inception until 10 October 2023 for prospective studies comparing the efficacy of SB and CIB. Meta-analysis using a random effects model was performed for three observational cohort studies, totalling 122 patients with 527 bronchoscopies. Overall, neither SB nor CIB had a higher likelihood of detecting acute lung transplant rejection of any grade. Subsequent subgroup analyses showed no advantage for SB in detecting minimal rejection (grade A1), but an inverse association was observed for higher-grade rejection. In conclusion, our study found no significant difference in detecting acute lung transplant rejection between SB and CIB. However, due to the limited number of studies and small sample sizes, larger prospective studies are urgently needed to definitely determine whether there truly exists no difference between SB and CIB in detecting acute rejection, particularly A1 minimal rejection.

Intragraft Hyaluronan Increases in Association With Acute Lung Transplant Rejection

Acute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients. The cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant. In analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32). These results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.

Protective Role of ECMO on Reperfusion Injury and Acute Rejection in Lung Transplantation: A Pathological Analysis

Purpose The routine utilization of intraoperative extracorporeal membrane oxygenation (ECMO) in lung transplantation is recently extensively investigated for its protective role, especially on reperfusion injury. The purpose of this study is to compare pathological features on pre and post-reperfusion biopsies and on 30 and 90-days surveillance trans-bronchial biopsies in lung transplantations performed with or without ECMO support to assess its protective role on the graft Methods 51 patients (13 with ECMO support, 38 without ECMO support) underwent bilateral lung transplantation at our Institution between 2012 and 2019. Only patients on ECMO at time of anesthetic induction or before the first clamping of the pulmonary artery were included. Patients submitted to graft volume reduction before lung reperfusion were excluded from the analysis.Intra-operative pre and post-reperfusion biopsies were collected to analyze edema, leucocyte margination and congestion/extravasation (score 0-3). The presence of acute rejection (grade A0-3, grade B0-2) diffuse alveolar damage (DAD), organizing pneumonia (OP) on 30 and 90-days trans-bronchial surveillance biopsies was also compared in the two groups. Results No significant differences were found between the two groups in terms of edema, leucocyte margination and congestion in pre reperfusion biopsies. On post reperfusion biopsies, leucocyte margination was significantly less frequent in ECMO group (46% vs 76%; p=0.043). A lower frequency of acute rejection (grade A0-3) was also found in the ECMO group on 30-days biopsies (25% vs 58%, p=0.047). Conclusion In conclusion, this analysis does not show significant differences between the two groups except for a lower frequency of leucocyte margination at post-reperfusion biopsies and acute rejection at 30-days biopsies in the ECMO group. Other studies, with a larger population, are needed in order to evaluate whether the positive clinical impact of using ECMO as a prevention of reperfusion edema after lung transplantation can also be explained by a defined pathological picture

OR53 Post transplant monitoring to include donor derived cell free DNA (%ddcfDNA): Steps toward personalized medicine

Aim Elevated %ddcfDNA levels have been shown to correlate with allograft injury and acute rejection in lung transplantation. This case highlights how conventional post-transplant monitoring may underestimate the complex interactions between infection, injury, and de novo donor specific antibody (DSA) development. Methods Quantitation of %ddcfDNA via next generation sequencing was performed as part of the Genomic Research Alliance for Transplantation (GRAfT) consortium. DSA monitoring utilized Luminex phenotype and single bead immunoassays. Spirometry was used to assess pulmonary function and transbronchial biopsies to assess rejection. Bronchoalveolar lavage, blood samples and sputum cultures were used to diagnose infections. Results A 60 year old male with interstitial lung disease received a single lobe lung transplant. This patient was entered into GRAfT, a blinded prospective trial to investigate the use of %ddcfDNA to monitor allograft injury and predict long term outcomes. Immediately after transplant, high %ddcfDNA was detected in the recipient’s plasma which declined over several weeks. A biopsy on post-operative day (POD) 192 indicated mild acute cellular rejection concomitant with an infection and a spike in %ddcfDNA. The elevated %ddcfDNA ( > 1% threshold) suggested substantial injury to the allograft despite stable lung function. The patient experienced several infections prior to the detection of HLA-DQB1 de novo DSA. The second %ddcfDNA spike was concurrent with an increase in DSA and loss in lung function. Therapeutic plasma exchange reduced DSA with corresponding %ddcfDNA regression and improved lung function. An infection on POD 338 correlated with a third %ddcfDNA spike (last available measurement). The patient experienced further infections with a diminishing trend in lung function. Conclusion %ddcfDNA monitoring to detect cumulative clinical and subclinical injury may aid in assessing de novo DSA risk and in the development of interventions to prevent chronic allograft loss. Download : Download high-res image (141KB) Download : Download full-size image A.M. Jackson: 3. Speaker’s Bureau; Company/Organization; Thermo Fisher Scientific. DRB4*01:03:01 DQA1*03:01:01 DQB1*03:02:01 DPA1*01:03:01 DPB1*04:02:01 (HF = 0.03). A new DPA1*02:07:01_5407G > A was found. Conclusions As we published previously, the DRB1*04-DQA1*03-DQB1*03 association is strong but it is shown for the first time, that A*, B*, C* DQA1* and DPB1* alleles of Mexican AMI ancestry are strongly associated. The genetics of VKH is undoubtedly of Oriental origin, and present therefore in AMI, admixed groups such as Hispanics, Mediterranean and Asians. The shared epitope at S57-LLEQRRAA 67-74 in DR β 1 chain and the new class I associations are the basis to look for immunological intervention to block the T-cell response vs. the antigens that trigger the autoimmune response in VKH.

CD8 T Effector Memory T Cells as Predictive Biomarker of Severe Acute Rejection in Lung Transplantation

Severe acute rejection (AR) after lung transplantation (LT) increases the risk of bronchiolitis obliterans syndrome with subsequent impairment in patient and graft survival. The identification of biomarkers to minimize AR rate and improve long term graft survival should be a priority in transplant field. Previously, the CD8 effector memory T (TEM) cells have been identified as a potential biomarker of acute rejection in patient awaiting for a lung transplantation(1). The aim of the study was to correlate CD8 TEM with severity of acute rejection after LT. Material and Methods 76 patients with end-stage lung disease were recruited from 2010 in our institution and prospectively followed after LT. Flow cytometry and monoclonal antibodies to identify CD8 T cell subsets in peripheral blood were used. Protocol biopsy at 21 day post transplantation was performed to identify acute rejection. Results and Discussion A total of 41 (54%) of LT recipients had acute rejection and 9 of them were severe (grade A3 or A4). Before transplant, the patients with severe acute rejection had significantly higher CD8 TEM/mm3 than no AR group (median 328.5; IQR: 187.2-507.6) vs (median 70.2; IQR: 49.3-123.8); p=0.027, whereas the levels of CD8 TEM in mild AR group are reduced compared with severe AR (median 95.4; IQR: 45.8 – 189.8); p=0.0748. The CD8 TEM levels pre-LT are increased in those with subsequent severe AR. Conclusion Monitoring the levels of CD8 TEM prior lung transplantation could identify patients at risk of suffering severe acute rejection. This biomarker should be validated in larger multicentre studies before be used in clinic. Reference San Segundo, D et al. PLoS One. 2013 Nov 13;8(11):e80601

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rabbit ATG in the Prophylaxis of Acute Rejection in Lung Transplantation

ATG-Fresenius S (ATG-F) is a polyclonal anti-human-T-lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG-F at doses of 5 and 9 mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow-up within 12 months of transplantation. The interim analysis showed the ATG-F 5 mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9 mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG-F 9 mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single-dose induction therapy with ATG-F within the first year after lung transplantation.

(172) - A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Study of Rabbit ATG in the Prophylaxis of Acute Rejection in Lung Transplantation

ATG-Fresenius S (ATG-F) is a polyclonal anti-human-T-lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG-F at doses of 5 and 9 mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow-up within 12 months of transplantation. The interim analysis showed the ATG-F 5 mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9 mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG-F 9 mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single-dose induction therapy with ATG-F within the first year after lung transplantation.

CMV driven CD8+ T-cell activation is associated with acute rejection in lung transplantation

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection.

Candidiasis invasora en una paciente sometida a retrasplante unipulmonar

BackgroundLung-graft loss is a potential problem for the majority of lung-transplant recipients. Retransplantation could be a treatment option, despite significant morbidity and mortality due to infectious complications. The epidemiology, clinical presentation and early treatment are still the basis of the overall approach to the fungal invasive infection after repeated transplant. Clinical caseThis is the case of a 29 year-old woman who underwent a left lung retransplantation due to bronchiolitis obliterans syndrome and developed Candida albicans invasive disease. She received the usual prophylaxis with nebulized liposomal amphotericin B and was also treated with anidulafungin. She received corticosteroid therapy and plasma exchange as acute lung transplant rejection was suspected with subsequent progressive deterioration and death. In the culture of blood samples yeasts were isolated, later identified as C. albicans resistant to fluconazole, caspofungin and micafungin (MCI 128μg/ml, 8μg/ml, 4μg/ml, respectively) and susceptible to anidulafungin and amphotericin B (MCI 0.25μg/ml, 0.5μg/ml, respectively). ConclusionsThe empirical management of acute transplant rejection with corticosteroid boluses and plasma exchange can help to spread the underlying and undiagnosed fungal infection. It is considered that an increase in the regular dose of anidulafungin is necessary after plasma exchange. To date, fungal echinocandin resistance did not seem to be a major cause for concern in the treatment of patients with invasive mycoses. However, there is increasing evidence of natural and acquired resistance resulting in life-threatening infections and clinical failure.

Increased expression of graft intraepithelial T-Cell pro-inflammatory cytokines compared with native lung during episodes of acute rejection

We have previously reported that T-cell pro-inflammatory cytokines in the airways are associated with acute lung transplant rejection. However, during acute rejection episodes, we found no significant differences in airway intraepithelial T cell pro-inflammatory cytokines from stable and rejecting patients due to broad cytokine variability between patient groups. To overcome this limitation, we hypothesized that there would be an increase in pro-inflammatory intraepithelial T-cells in the graft compared with native airway during acute rejection. Bronchial brushings from patients with stable graft function, evidence of acute rejection, bronchiolitis obliterans syndrome, infection, and healthy controls were stimulated and pro-inflammatory cytokines in intraepithelial T cells from graft and native airway were determined using multiparameter flow cytometry. There was a significant increase in intraepithelial T-cell interferon-γ and tumor necrosis factor (TNF)-α in the graft of patients with acute rejection compared with intraepithelial T cells obtained from the native airway, but no changes were noted among other patient groups. The increase in intraepithelial T-cell TNF-α was more pronounced the higher the acute rejection grade. The graft airway epithelium is enriched with T cells producing interferon-γ and TNF-α during acute graft rejection. Therapeutic targeting of these pro-inflammatory cytokines and improved monitoring using this assay may reduce acute lung transplant rejection.

253 Human Leukocyte Antigen-G Concentrations in Plasma and BALF Are Inversely Correlated to High Grade Acute Rejection in Lung Transplantation

253 Human Leukocyte Antigen-G Concentrations in Plasma and BALF Are Inversely Correlated to High Grade Acute Rejection in Lung Transplantation

Lymph Angiogenesis After Lung Transplantation and Relation to Acute Organ Rejection in Humans

Acute rejection after kidney transplantation was found to be associated with increased recipient-derived lymph angiogenesis. However, the relation of lymph angiogenesis to acute rejection in lung transplantation has not yet been investigated. Transbronchial biopsies from 23 lung transplant recipients (47 + or - 15 years old, 15 male, 19 double lungs, 4 single lungs), taken at 14 and 90 days after transplantation were investigated. Immunohistostaining for PROX-1 (an lymphatic endothelial marker) and for vascular endothelial growth factor receptor (VEGFR) 1 and 2 (blood capillary markers) was performed. Biopsies with no sign of rejection (International Society for Heart and Lung Transplantation [ISHLT] grade A0, n = 27) were compared with biopsies with rejection grade A1/A2 (n = 19). Biopsies with ISHLT rejection grade A1 or A2 showed a significantly higher density of PROX-1 marked lymphatics in comparison with biopsies of grade A0 at 14 days (p < 0.001) and at 90 days (p < 0.001) after transplantation, and in the collective comparison (all biopsies with ISHLT grade A1 or A2 versus all biopsies with grade A0, p < 0.001). For VEGFR-1 and VEGFR-2, no difference was found between ISHLT grade A1 or A2 compared with grade A0, neither at 14 or 90 days nor in the collective comparison. Increased lymphatic angiogenesis after lung transplantation, demonstrated by increased density of the PROX-1 lymphatic endothelial marker, was associated with histologically evident acute organ rejection in humans. Although the exact role of lymphatic angiogenesis in acute organ rejection remains to be determined, further study of the interaction between the microvasculature and acute rejection seems warranted. Pending further investigation, analysis of PROX-1 density may develop into a new tool for rejection monitoring, supplementing conventional rejection grading.

Transfer of Tolerance to Collagen Type V Suppresses T-Helper-Cell-17 Lymphocyte-Mediated Acute Lung Transplant Rejection

Rat lung allograft rejection is mediated by collagen type V (col(V)) specific T-helper-cell 17 (Th17) cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. Therefore, we tested whether regulatory T cells from tolerant rats could suppress the Th17-mediated rejection in the syngeneic model of lung transplantation. Rats were subjected to syngeneic left lung transplantation, and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous injection of col(V), and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-positron emission tomography imaging and histochemistry. The transvivo delayed type hypersensitivity assay was used to analyze the Th17 response. Adoptive cotransfer of col(V)-specific effector cells with cells from col(V)-tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of interleukin (IL)-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by transvivo delayed type hypersensitivity showed that the reactivity to col(V) was dependent on the presence of tumor necrosis factor-alpha and IL-17 but not interferon-gamma. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection. Th17-mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment, therefore, should target Th17 development and not suppression of T-cell activation by suppressing IL-2.

Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation

Lung transplantation (LT) has become an accepted therapy for selected patients with advanced lung disease. One of the main limitations to successful LT is rejection of the transplanted organ where chemokines are pivotal mediators. Here, we test the relationship between copy number variation (CNV) in the CCL4L chemokine gene and rejection risk in LT patients (n=161). Patients with no acute rejection showed a significantly lower mean number of CCL4L copies than patients that showed acute rejection (1.66 vs 1.96, P=0.014), with an even greater number of gene copies seen in patients with more than one episode of acute rejection (1.66 vs 2.30, P=0.001). Additionally, patients with > or =2 CCL4L copies had a significantly higher risk of acute rejection compared with patients that had 0-1 CCL4L copies (odds ratio 2.65; 95% confidence interval, 1.33-5.28; P=0.0046). A combined analysis of CCL4L CNV and the rs4796195 CCL4L single nucleotide polymorphism demonstrated that the effect of CCL4L copy number in acute rejection is mainly because of the number of copies of the CCL4L1 allelic variant. This finding constitutes the first report of CNV as a correlate factor in allograft rejection.

24: Cytomegaloviral and Rhinoviral Co-Infection Is a Distinct Risk for Acute Rejection in Lung Transplantation

24: Cytomegaloviral and Rhinoviral Co-Infection Is a Distinct Risk for Acute Rejection in Lung Transplantation

Acute Lung Transplant Rejection Is Associated With Localized Increase in T-Cell IFNγ and TNFα Proinflammatory Cytokines in the Airways

Allograft rejection remains a major cause of morbidity and mortality after lung transplantation and is associated with increased gene expression for proinflammatory cytokines. T cells are a major cell type involved in graft rejection. There have been no previous studies of cytokine production by T cells from blood, bronchoalveolar lavage (BAL), and intraepithelial T cells from bronchial brushings (BB) during rejection episodes; we hypothesized that T-cell proinflammatory cytokines would be increased in the airways during rejection episodes despite standard immunosuppression regimens. To investigate changes in cytokine profiles during rejection episodes, whole blood, BAL, and BB from stable lung transplant patients and those with acute rejection were stimulated in vitro and intracellular cytokine production by CD8- (CD4+) and CD8+ T-cell subsets determined using multiparameter flow cytometry. Transforming growth factor (TGF)-beta was significantly decreased in blood CD4+ and CD8+ T cells while interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha were significantly increased in BAL CD4+ and CD8+ T cells in patients with evidence of rejection. There was no change in CD4:CD8, interleukin (IL)-2, or IL-4 between stable and rejecting groups. Acute lung transplant rejection is associated with decreased intracellular T-cell TGFbeta in blood and increased intracellular IFNgamma and TNFalpha in BAL CD4+ and CD8+ T cells. Drugs that effectively reduce airway T-cell IFNgamma and TNFalpha proinflammatory cytokine production may improve current protocols for reducing acute graft rejection in lung transplant patients.

Elevation of Interleukin-15 Protein Expression in Bronchoalveolar Fluid in Acute Lung Allograft Rejection

Background:Acute rejection remains a major source of morbidity in lung transplantation. Although interleukin (IL)-2 has been the principal T-cell growth factor implicated in acute rejection, IL-2 blockade does not prevent acute rejection completely. Recently, IL-15, a stromal cell-derived cytokine, has been found to share a similar biological function with IL-2. We hypothesized that IL-15 levels may be elevated in acute lung rejection in the presence of IL-2 blockade.Methods:Acute allograft rejection developed in 21 of 42 lung transplant recipients. BAL fluid (BALF) was analyzed for IL-2 and IL-15 protein expression by standard enzyme-linked immunosorbent assay.Results:The average (± SD) BALF IL-15 level was higher in lung transplant recipients with acute rejection compared to those without rejection (25 ± 25 pg/mL vs 4.5 ± 1.5 pg/mL, respectively; p < 0.0001). In addition, there appeared to be a bimodal distribution of BALF IL-15 levels in lung transplant recipients with acute rejection. BALF IL-2 levels were not associated with acute rejection. BALF IL-15 levels were not associated with bacterial, fungal, or cytomegalovirus infection.Conclusion:These data show that BALF IL-15 levels are elevated in acute lung allograft rejection in the presence of IL-2 receptor blockade and may be an important mediator for acute rejection in lung transplantation.

Subendothelial C4d deposition and intragraft B cell infiltrates are associated with high-grade acute rejection in lung transplantation

The aim of this study was to evaluate the B cell profiles and antibody-mediated rejection in lung transplant recipients (LT) pretreated with antilymphoid antibody preparations (Thymoglobulin or Campath, see table).

Immunosuppressive effects of FK506 inhalant on acute rejection in lung transplantation

Background: FK506 0.1% inhalant was recently developed for localized administration. In this study, we investigated its effects on acute lung allograft rejection, and compared its efficacy with that of FK506 intramuscular injection.

New combination of immunosuppressive therapy decreases acute rejection in lung transplantation

Introduction: Several new immunosuppressive agents have been developed to improve graft and ultimately, patient survival. The impact of these agents has not been well documented in the lung transplantation. We assessed the safety and efficacy of three different immunosuppressive regimens in lung transplant recipients.