Elbert Kuo

Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection

BACKGROUND Primary graft dysfunction (PGD) in the immediate post-lung transplant period strongly increases the risk of chronic rejection (broncholitis obliterans syndrome). Here, we hypothesized that PGD-induced inflammation augments alloimmunity, thereby predisposing to broncholitis obliterans syndrome. METHODS Primary graft dysfunction and broncholitis obliterans syndrome were diagnosed according to the established International Society for Heart and Lung Transplantation criteria. Anti-human leukocyte antigen (HLA) alloantibodies were analyzed using Flow-PRA. Donor HLA class II-specific T cells were analyzed using interferon (IFN)-gamma ELISPOT. Serum levels of 25 cytokines and chemokines were measured using LUMINEX. RESULTS Of the 127 subjects, 29 (22.8%) had no PGD (grade 0), 42 (33.2%) had PGD-1, 36 (28.3%) had PGD-2, and 20 (15.7%) had PGD-3. Patients with PGD grades 1 to 3 (PGD(1-3)) had elevated proinflammatory mediators MCP-1, IP-10, interleukin (IL)-1 beta, IL-2, IFN-gamma, and IL-12 in the sera during the early posttransplant period compared with patients with PGD grade 0 (PGD(0)). On serial analysis, PGD(1-3) patients revealed increased development of de novo anti-HLA-II (5 years: 52.2% versus PGD(0) 13.5%, p = 0.008). However, no difference was found in anti-HLA-I alloantibody development (PGD(1-3) patients 48% versus PGD(0) 39.6%, p = 0.6). Furthermore, PGD(1-3) patients had increased frequency of donor HLA class II-specific CD4(+) T cells [(91.4 +/- 19.37) x 10(-6) versus (23.6 +/- 15.93) x 10(-6), p = 0.003]. CONCLUSIONS Primary graft dysfunction induces proinflammatory cytokines that can upregulate donor HLA-II antigens on the allograft. Increased donor HLA-II expression along with PGD-induced allograft inflammation promotes the development of donor specific alloimmunity. This provides an important mechanistic link between early posttransplant lung allograft injury and reported association with broncholitis obliterans syndrome.

Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation

Abstract:  Lung transplantation is recognized as the only viable treatment option in a variety of end‐stage pulmonary diseases. However, the long‐term survival after lung transplantation is limited by the development of obliterative bronchiolitis, and its clinical correlate bronchiolitis obliterans syndrome (BOS), which is considered to represent chronic lung allograft rejection. Histopathologically, BOS is an inflammatory process that leads to fibrous scarring of the terminal and respiratory bronchioles and subsequent total occlusion of the airways. The specific etiology and pathogenesis of BOS are not well understood. The current premise is that BOS represents a common lesion in which different inflammatory insults such as ischemia‐reperfusion, rejection, and infection can lead to a similar histological and clinical outcome. However, the low incidence of BOS in non‐transplanted individuals and the observation that early development of BOS is predicted by the frequency and severity of acute rejection episodes indicate that alloimmune‐dependent mechanisms play a crucial role in the pathogenesis of BOS. The evidence presented in this review indicates that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft. This process is aggravated by alloimmune‐independent mechanisms such as ischemia‐reperfusion and infection. Currently, treatment of BOS is frequently unsuccessful. Therefore, a better understanding of the immunopathogenesis of BOS is of paramount importance toward improving long‐term patient and graft survival after lung transplantation.

Molecular mechanisms of chronic rejection following transplantation.

Although significant advances have been made in the field of organ transplantation, chronic rejection remains a major limiting factor for prolonged graft survival. The long-term survival and function of transplanted lungs are limited by the development of bronchiolitis obliterans syndrome (BOS). The 10-yr lung graft survival rate is only 18.6%. Aside from results of several clinical studies that strongly support the concept that BOS results from alloimmune-mediated injury, little is known regarding specific immune effectors or target molecules involved in the pathogenesis of BOS. Studies from our laboratory have provided evidence for the seminal role of CD4+ T-cells in the pathogenesis of obliterative airway disease (OAD) seen in BOS. Prior to any clinically detectable lesions, there is indirect antigen presentation of mismatched major histocompatibility complex (MHC) class I antigen and production of antibodies to these MHC antigens. Both MHC and minor histocompatibility antigen disparities can result in the development of OAD in animal models and preliminary results strongly suggest that peptide vaccination strategies may prevent OAD following heterotopic tracheal transplants. Using a newly developed orthotopic tracheal transplant model, we have obtained evidence for an important and probably exclusive role for airway epithelial cell injury as a primary mechanism for the immunopathogenesis of the development of OAD.

Impact of Video-Assisted Thoracoscopic Surgery on Benign Resections for Solitary Pulmonary Nodules

BACKGROUND Differentiating benign from malignant pulmonary lesions is an important part of surgical decision making. We reviewed our experience of resecting suspicious pulmonary nodules to test the hypothesis that the increased use of video-assisted thoracic surgery (VATS) has increased the resection rate of benign lesions. METHODS A retrospective analysis was carried out on 3,217 patients who underwent resection for focal pulmonary lesions between 1995 and 2009. Resection method, computed tomography (CT) results, positron emission tomography (PET) results, and operative and pathology reports were reviewed. RESULTS Pulmonary resection was by thoracotomy/median sternotomy in 2,632 of 3,217 (82%) patients and by VATS in 585 of 3,217 (18%). Resections performed by VATS increased from 129 of 2,150 (6%) between 1995 and 2005 to 453 of 1,067 (42.4%) between 2006 and 2009. From 2006 to 2009, 31.4% of lobectomies and 63.9% of wedge resections were performed by VATS. Benign lesions were found in 350 of 3,217 (10.8%) patients. Between 1995 and 2005 our resection rate of benign lesions was 192 of 2,150 (8.9%). From 2006 to 2009, it increased to 158 of 1,067 (14.8%), of which 85 of 456 (20.8%) were VATS and 63 of 611(10.3%) were open procedures. The benign lesion resection rate was 91 of 237 (38.3%) for VATS wedges, 49 of 134 (36.6%) for open wedges, 4 of 219 (1.8%) for VATS lobectomies, and 14 of 477 (2.9%) for open lobectomies. 257 of 456 (52.0%) of the VATS resections were wedges compared with 134 of 611 (21.9%) of the open procedures. CONCLUSIONS There has been an increase in pulmonary resections performed by VATS. This is associated with an increase in benign lesion resections. The benign lesion resection rate for VATS was twice that of the open procedure rate. However the benign lesion resection rates for wedge resections and lobectomies were not significantly different in regard to approach. VATS has led to an increase in our overall benign lesion resection rate, which can be explained by the increased number of VATS wedge resections that are being performed.

Respiratory Virus-Induced Dysregulation of T-Regulatory Cells Leads to Chronic Rejection

BACKGROUND Lower respiratory viral infections predispose to bronchiolitis obliterans syndrome (BOS). In addition, there is emerging evidence to support the role of autoimmunity in the pathogenesis of BOS. Because CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Treg) control autoimmunity, we tested the hypothesis that respiratory virus-induced Treg dysfunction leads to BOS. METHODS Treg frequency was monitored using flow cytometry. Apoptosis, cytokines, and antibodies were analyzed using annexin V assay, LUMINEX, and enzyme-linked immunosorbent assay, respectively. Murine studies were performed using the orthotopic tracheal transplant model. RESULTS (A) Human studies: Treg troughs (decrease >50% of baseline) were found in 13 (43.3%) of 30 lung transplant recipients. Treg isolated during troughs revealed increased apoptosis (37.8%). Patients with Treg troughs had increased prevalence of antibodies to self-antigens collagen type I (23.1% vs 5.8% pretrough), collagen V (7.7% vs 0%), and k-alpha tubulin (30.7% vs 11.7%, p < 0.01) at 6 months post-trough. Increased number of Treg troughs correlated with more rapid onset of BOS. (B) Murine studies: Infection of tracheal transplant recipients with murine parainfleunza sendai virus led to increased Treg apoptosis (50.5%) in the draining lymph nodes. Vaccination against sendai virus prior to transplant abrogated apoptosis of Treg. In vitro, sendai virus-infected, but not naive, tracheal epithelial cells demonstrated upregulation of FasL (>3.5-fold) and induction of co-cultured Treg apoptosis (5.6-fold increase). CONCLUSIONS Respiratory viral infections cause Treg apoptosis which leads to the development of de novo autoimmunity that may play a role in the pathogenesis of BOS.

Animal models for bronchiolitis obliterans syndrome following human lung transplantation.

Lung transplantation is the only viable treatment option that can improve survival and enhance the quality of life of patients with end-stage lung diseases such as emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, and primary pulmonary hypertension. However, the long-term survival of lung allografts is still limited by the development of bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy. BOS is the most significant cause of long-term morbidity and mortality after lung transplantation. Over the past decade, several animal models have been developed to investigate BOS. These are valuable to elucidate the immunologic and pathologic mechanisms that lead to BOS and to test treatment options for BOS. In this review, we discuss the advantages and disadvantages of different animal models and highlight work that has been done with each model.

Lung Herniation After Supraclavicular Thoracic Outlet Decompression

Lung herniation after first rib resection for thoracic outlet syndrome (TOS) has not been reported to our knowledge. We present a unique case of cervical lung herniation causing displacement of the brachial plexus and chronic pain in a patient who had previously undergone supraclavicular thoracic outlet decompression with first rib resection. This was successfully treated with thoracoscopic reduction and resection of the herniated lung and pleural flap closure of the defect.

Recurrent Subcutaneous Air of the Face and Neck

Subcutaneous air of the face and neck can be seen after trauma to the lungs, airway, and esophagus. We present a case of a 29-year-old with recurrent subcutaneous air of the face and neck with minimal pneumomediastinum. In this report, we discuss the workup of this patient and review the literature regarding self-inflicted causes.