Teruaki Mizobuchi

Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection

We have reported that lung allograft rejection involves an immune response to a native protein in the lung, type V collagen (col(V)), and that col(V)-induced oral tolerance prevented acute and chronic rejection. In support of these findings col(V) fragments were detected in allografts during rejection, but not in normal lungs. The purpose of the current study was to isolate and characterize col(V)-specific allograft-infiltrating T cells and to determine their contribution to the rejection response in vivo. Two col(V)-specific T cell lines, LT1 and LT3, were isolated from F344 (RT1lv1) rat lung allografts during rejection that occurred after transplantation into WKY (RT1l) recipients. Both cell lines, but not normal lung lymphocytes, proliferated in response to col(V). Neither LT1 nor LT3 proliferated in response to alloantigens. LT1 and LT3 were CD4+CD25− and produced IFN-γ in response to col(V). Compared with normal CD4+ T cells, both cell lines expressed a limited V-β TCR repertoire. Each cell strongly expressed V-β 9 and 16, but differed in expression of other V-βs. Adoptive transfer of each cell line did not induce pathology in lungs of normal WKY rats. In contrast, adoptive transfer of LT1, but not LT3, caused marked peribronchiolar and perivascular inflammation in isograft (WKY) lungs and abrogated col(V)-induced oral tolerance to allograft (F344) lungs. Collectively, these data show that lung allograft rejection involves both allo- and autoimmune responses, and graft destruction that occurs during the rejection response may expose allograft-infiltrating T cells to potentially antigenic epitopes in col(V).

Anti-Type V Collagen Lymphocytes that Express IL-17 and IL-23 Induce Rejection Pathology in Fresh and Well-Healed Lung Transplants

Immunity to collagen V [col(V)] contributes to lung ‘rejection.’ We hypothesized that ischemia reperfusion injury (IRI) associated with lung transplantation unmasks antigenic col(V) such that fresh and well‐healed lung grafts have differential susceptibility to anti‐col(V)‐mediated injury; and expression of the autoimmune cytokines, IL‐17 and IL‐23, are associated with this process. Adoptive transfer of col(V)‐reactive lymphocytes to WKY rats induced grade 2 rejection in fresh isografts, but induced worse pathology (grade 3) when transferred to isograft recipients 30 days post‐transplantation. Immunhistochemistry detected col(V) in fresh and well‐healed isografts but not native lungs. Hen egg lysozyme‐reactive lymphocytes (HEL, control) did not induce lung disease in any group. Col(V), but not HEL, immunization induced transcripts for IL‐17 and IL‐23 (p19) in the cells utilized for adoptive transfer. Transcripts for IL‐17 were upregulated in fresh, but not well‐healed isografts after transfer of col(V)‐reactive cells. These data show that IRI predisposes to anti‐col(V)‐mediated pathology; col(V)‐reactive lymphocytes express IL‐17 and IL‐23; and anti‐col(V)‐mediated lung disease is associated with local expression of IL‐17. Finally, because of similar histologic patterns, the pathology of clinical rejection may reflect the activity of autoimmunity to col(V) and/or alloimmunity.

Differential Expression of Smad7 Transcripts Identifies the CD4+CD45RChigh Regulatory T Cells That Mediate Type V Collagen-Induced Tolerance to Lung Allografts

Regulatory T cells (Tregs) induced by oral tolerance may suppress immunity by production of TGF-β that could also enhance Treg activity. However, all cells that are phenotypically Tregs in rats (CD4+CD45RChigh-RChigh) may not have regulatory function. Because Smad7 expression in T cells is associated with inflammation and autoimmunity, then lack of Smad7 may identify those cells that function as Tregs. We reported that feeding type V collagen (col(V)) to WKY rats (RT1l) induces oral tolerance to lung allografts (F344-RT1lvl) by T cells that produce TGF-β. The purpose of the current study was to identify the Tregs that mediate col(V)-induced tolerance, and determine Smad7 expression in these cells. RChigh cells from tolerant rats were unresponsive to allogeneic stimulation and abrogated rejection after adoptive transfer. In contrast, CD4+CD45RClow (RClow) cells from tolerant rats and RChigh or RClow cells from normal rats or untreated allograft recipients proliferated vigorously in response to donor Ags, and did not suppress rejection after adoptive transfer. TGF-β enhanced proliferation in response to col(V) presented to tolerant RChigh, but not other cells. In contrast to other cells, only RChigh cells from tolerant rats did not express Smad7. Collectively, these data show that the Tregs that mediate col(V)-induced tolerance to lung allografts do not express SMAD7 and, therefore, are permissive to TGF-β-mediated signaling.

Pulmonary resection for lung cancer with malignant pleural disease first detected at thoracotomy

OBJECTIVES The prognosis of non-small-cell lung cancer (NSCLC) patients with malignant pleural disease (MPD), characterized by malignant pleural effusion and/or malignant pleural nodules, is reported to be poor, and patients with MPD are generally not subjected to surgery. However, whether or not the primary tumor should be resected, when MPD is first detected at thoracotomy, is controversial. METHODS The clinical records of 1623 consecutive NSCLC patients, who underwent surgery between 1990 and 2007, were retrospectively reviewed. A hundred patients (6.2%) were classified with pathological stage IV disease according to the seventh edition of the Union for International Cancer Control (UICC) staging system. There were 73 patients with MPD, which included 32 with effusion without nodules (MPE) and 41 with nodules with or without effusion (MPN). Intra- or postoperative pleural chemotherapy was administered to 37 MPD patients. RESULTS The median survival time, the 3-year survival rate and the 5-year survival rate for MPD patients were 25.9 months, 41.4%, and 23.7%, respectively, which are better outcomes than those for M1b patients (8.7 months, 18% and 18%, respectively) (log-lank test: p=0.014). Among MPD patients, N0-1 disease was determined to be a favorable prognostic factor (p=0.01). MPD status (MPE or MPN) was not prognostically significant (p=0.40). MPE patients with N0-1 disease had a significantly better prognosis with a 5-year survival rate of 63.6% compared to MPE patients with N2-3 disease (p=0.003). Twenty-seven percent of MPN patients with N0-1 disease achieved 5-year survival, whereas none of the MPD patients with N2-3 disease survived longer than 5 years after surgery. CONCLUSIONS The prognosis of patients with surgically detected MPD, who underwent resection, was better than that of M1b patients. MPE patients with N0-1 disease may be candidates for resection.

A Total Pleural Covering for Lymphangioleiomyomatosis Prevents Pneumothorax Recurrence

Background Spontaneous pneumothorax is a major and frequently recurrent complication of lymphangioleiomyomatosis (LAM). Despite the customary use of pleurodesis to manage pnenumothorax, the recurrence rate remains high, and accompanying pleural adhesions cause serious bleeding during subsequent lung transplantation. Therefore, we have developed a technique of total pleural covering (TPC) for LAM to wrap the entire visceral pleura with sheets of oxidized regenerated cellulose (ORC) mesh, thereby reinforcing the affected visceral pleura and preventing recurrence. Methods Since January 2003, TPC has been applied during video-assisted thoracoscopic surgery for the treatment of LAM. The medical records of LAM patients who had TPC since that time and until August 2014 are reviewed. Results TPC was performed in 43 LAM patients (54 hemithoraces), 11 of whom required TPC bilaterally. Pneumothorax recurred in 14 hemithoraces (25.9%) from 11 patients (25.6%) after TPC. Kaplan-Meier estimates of recurrence-free hemithorax were 80.8% at 2.5 years, 71.7% at 5 years, 71.7% at 7.5 years, and 61.4% at 9 years. The recurrence-free probability was significantly better when 10 or more sheets of ORC mesh were utilized for TPC (P = 0.0018). TPC significantly reduced the frequency of pneumothorax: 0.544 ± 0.606 episode/month (mean ± SD) before TPC vs. 0.008 ± 0.019 after TPC (P<0.0001). Grade IIIa postoperative complications were found in 13 TPC surgeries (24.1%). Conclusions TPC successfully prevented the recurrence of pneumothorax in LAM, was minimally invasive and rarely caused restrictive ventilatory impairment.

Clear cell tumor of the lung: surgical and immunohistochemical findings

We encountered a clear cell tumor of the lung (CCTL) that was located peripherally, adjacent to the visceral pleura. The tumor could be directly observed during surgery. We believe that this case report describing the surgical and related pathological findings is highly informative. A chest radiograph during routine examination of an asymptomatic 65-year-old woman being treated for hypertension and hyperlipidemia revealed a nodular shadow in the left lung field. Wedge resection was performed by video-assisted thoracic surgery. The in vivo color of the tumor was red, suddenly changing to white after the tumor was clamped. Pathology examination showed a uniform pattern consisting of large clear cells without cytologic atypia or increased mitotic activity. Immunohistochemistry revealed tumor cells positive for vimentin and melanocytic markers (HMB-45 and melan-A) and negative for epithelial membrane antigen and cytokeratin. With the absence of clinical findings in both kidneys, the tumor was diagnosed as a benign CCTL.

A strategy of sequential therapy with a bronchoscopic excision and thoracotomy for intra- and extrabronchial wall schwannoma: report of a case.

A 69-year-old woman was admitted with dyspnea on effort and left lung atelectasis on chest X-ray. Fiberoptic bronchoscopy revealed a complete obstruction of the left main bronchus due to a polypoid lesion. This lesion was diagnosed to be a schwannoma arising from the left lower bronchus. Bronchoscopic treatments were performed with electrosurgical snaring and the intratumoral injection of 99.5% ethanol. These treatments were performed once per week for 4 weeks, then were followed with a one-time application of semiconductor laser cautery. These treatments opened the airway and restored the left lung expansion. However, a residual tumor remained at the bifurcation of the left basal bronchus and B6. A cautious follow-up was conducted because schwannoma is a potentially benign tumor. A follow-up bronchoscopic examination at 21 months revealed a regrowth of the residual tumor. A complete resection using a left S6 sleeve segmentectomy was thus performed. The pathologic diagnosis of the tumor was benign schwannoma. There were no complications and no evidence of disease recurrence has been observed after the surgery.

Clinical characteristics of catamenial and non‐catamenial thoracic endometriosis‐related pneumothorax

A major pathogenic factor for catamenial pneumothorax is thoracic endometriosis. However, thoracic endometriosis‐related pneumothorax (TERP) can develop as either catamenial or non‐catamenial pneumothorax (CP). Therefore, the aim of this study was to elucidate the clinical differences between catamenial and non‐catamenial TERP.

Comparison between endobronchial ultrasound-guided transbronchial needle aspiration and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of postoperative nodal recurrence in patients with lung cancer

OBJECTIVES Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value for preoperative mediastinal staging in patients with lung cancer. In this study, the utility of EBUS-TBNA for the pathological diagnosis of postoperative lymph node recurrence was investigated and compared with that of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS Patients who received both EBUS-TBNA and FDG-PET for the diagnosis of postoperative lymph node recurrence were retrospectively investigated. They underwent routine chest computed tomography (CT) follow-up after thoracotomy, and when hilar or mediastinal lymph nodes showed enlargement on CT compared with the previous chest CT, they were referred for FDG-PET and EBUS-TBNA. We compared the diagnostic performance of these two modalities. In addition, pathological findings of the biopsied sample were evaluated precisely and compared with the results of FDG-PET. Positivity for hypermetabolism on FDG-PET was defined as a standardized uptake value (SUV) greater than 2.5. RESULTS A total of 40 patients were retrospectively reviewed. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of EBUS-TBNA were 100% for each parameter, whereas those of FDG-PET were 95.8, 12.5, 62.2, 66.7 and 62.5%, respectively. The SUV of true-positive nodes was significantly higher than that of false-positive nodes (P = 0.001). Twenty-two of 24 patients who were confirmed for recurrence by EBUS-TBNA underwent anticancer treatment. The pathological diagnoses of 14 false-positive cases by FDG-PET were chronic inflammation in 12 and non-specific granuloma in 2. CONCLUSIONS The diagnostic yield of EBUS-TBNA is higher than that of FDG-PET when postoperative lymph node recurrence is suspected.

Pleural Covering Application for Recurrent Pneumothorax in a Patient with Birt-Hogg-Dubé Syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary disease that presents with multiple lung cysts and recurrent pneumothorax. These cysts occupy predominantly the lower-medial zone of the lung field adjacent to the interlobar fissure, and some of them abut peripheral pulmonary vessels. For the surgical management of pneumothorax with BHDS, the conventional approach of resecting all subpleural cysts and bullae is not feasible. Thus, after handling several bullae by using a stapler or performing ligation as a standardized treatment, we applied to a pleural covering technique to thicken the affected visceral pleura and then to prevent recurrence of pneumothorax. We herein report the successful application of a pleural covering technique via thoracoscopic surgery to treat the recurrent pneumothorax of a 30-year-old man with BHDS. This technique is promising for the management of intractable pneumothorax secondary to BHDS.