Eero Taskinen

Human Herpesvirus-6 Infection After Liver Transplantation

A diagnosis of posttransplantation human herpesvirus-6 (HHV-6) infection was established for eight adult recipients among a liver transplantation patient population of 121. The diagnosis was based on serology and demonstration of HHV-6 specific antigens in liver biopsy specimens with use of monoclonal antibodies and immunoperoxidase staining. A significant graft dysfunction was recorded in association with serodiagnosis. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected retrospectively in all six available liver biopsy specimens. Histologic examination of biopsy specimens demonstrated acute rejection in 5 of the 8 patients, and 3 patients had portal lymphocyte infiltration. In five cases cytomegalovirus (CMV) infection was associated with HHV-6 infection; in four cases CMV antigens were also detected in the biopsy specimens. Two patients who had pure HHV-6 infection without CMV infection or rejection had significantly impaired graft function, with a positive antigen-detection test. Thus, HHV-6 may infect the liver allograft and cause graft dysfunction and may possibly be associated with rejection and/or CMV infection.

Colorectal Dysplasia and Carcinoma in Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis

BACKGROUNDnThe aim of this study was to evaluate the role of primary sclerosing cholangitis (PSC) as a cofactor in the dysplasia-carcinoma sequence in ulcerative colitis (UC).nnnMETHODSnForty-five patients with UC and concomitant PSC and 45 pair-matched control patients with UC only were examined for colorectal dysplasia and carcinoma.nnnRESULTSnThe median duration of UC was 11 years in the group with UC and PSC and 15 years in the control group. Thirteen of the 45 patients (29%) with UC and PSC had colorectal neoplasia: 4, carcinoma; 2, high-grade dysplasia; and 7, low-grade dysplasia. Four of the 45 control patients (9%) had neoplastic findings: 1, carcinoma; 1, high-grade dysplasia, and 2, low-grade dysplasia (P < 0.05).nnnCONCLUSIONnThe results suggest that the risk of colorectal dysplasia and carcinoma in patients with UC is increased by concomitant PSC.

Human herpesvirus-6 infection is associated with adhesion molecule induction and lymphocyte infiltration in liver allografts

BACKGROUND/AIMSnHuman herpesvirus-6 (HHV-6) infection has been recently described in liver transplants. HHV-6 may infect the transplant and cause graft dysfunction. Some association between HHV-6 and rejection has also been recorded. We have now investigated the possible involvement of HHV-6 in the intragraft immunological processes, adhesion molecules induction and lymphocyte activation.nnnMETHODSnHHV-6 was detected in liver biopsies of 19 patients transplanted in the period from 1996 to 2000. Patients with other infections or rejection were excluded from the study. Finally, 19 biopsies of eight allografts with pure HHV-6 infection were available. Adhesion molecules (ICAM-1, VCAM-1, ELAM-1) and their ligands (LFA-1, VLA-4, sLeX) and lymphoid activation markers (MHC class II, IL-2R) were demonstrated in liver biopsies by immunohistochemistry. Five biopsies from patients with normal graft function and without rejection or infection were used as controls for immune staining, and ten biopsies with acute rejection but without infection were used as positive controls.nnnRESULTSnBiopsy histology demonstrated mild to moderate lymphocyte infiltration associated with HHV-6 infection. HHV-6 significantly (P < or = 0.05) increased the vascular expression of ICAM-1 and VCAM-1, and the number of graft infiltrating lymphocytes positive for LFA-1, VLA-4 and class II antigens. A total of 3/8 grafts developed chronic rejection.nnnCONCLUSIONSnHHV-6 infection increased adhesion molecule expression and lymphocyte infiltration in liver allografts.

Prevention of small airway obliteration in a swine heterotopic lung allograft model

BACKGROUNDnIn our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin.nnnMETHODSnDonor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months.nnnRESULTSnTotal epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis.nnnCONCLUSIONSnUnlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Histopathological findings in renal allografts at time of transplantation and correlation with onset of graft function

Histopathological changes quantified using the chronic allograft damage index (CADI) have been shown to predict subsequent graft outcome and developing chronic rejection. The aim of the study reported here was to investigate the extent to which cadaveric renal allografts exhibit histopathological changes at time of transplantation, focusing on changes covered by the CADI. We also analysed whether any histopathological change predicts delayed graft function. One hundred and twenty‐eight cadaveric kidney allografts with adequate protocol biopsy were studied. Tubular epithelial anisometric vacuolization was the commonest change, found in 62% of grafts and scored moderate or severe in 28% of these cases. Other prevalent changes were interstitial fibrosis, vascular hyalinosis, glomerular sclerosis and tubular basement‐membrane thickening in 40%, 37%, 28% and 22% of biopsies, respectively. Intensities were, however, scored as mild in over 95% of specimens. The mean CADI for all grafts was 0.74. A significant difference in CADIs was seen between grafts from donors under and over 40 years of age. Grafts with early, delayed and no function had a similar incidence of histopathological changes. Histopathological changes in renal allografts were mostly uncommon and mild at time of transplantation, but some grafts exhibited changes which were quantified using the CADI. Though histopathological changes quantified with the CADI are predictive of subsequent graft function, they did not affect onset of graft function.

Endothelin in Bronchoalveolar Lavage Fluid is Increased in Lung-Transplanted Patients

Animal studies have shown increased endothelin in bronchoalveolar lavage (BAL) fluid during unmodified rejection. We performed radioimmunoassay of endothelin in 59 BAL fluid samples from ten patients at different times after lung transplantation. All patients received immunosuppressive therapy (cyclosporin, azathioprine and methylprednisolone). Reference BAL samples were obtained from six controls. Of the 59 test samples, five were collected during rejection episodes, confirmed by clinical outcome, BAL cytology and radiology (rejection group), and 19 were taken during bacterial, viral or fungal infection (infection group). The endothelin content of BAL (pg/ml) was significantly greater in the rejection group than in the infection group (61.1 +/- 3.8 vs 40.6 +/- 2.0) or in the 35 samples taken in uncomplicated course after lung transplantation (40.9 +/- 5.4), p < 0.01. The endothelin level in BAL fluid from the controls was only 3.0 +/- 1.4 pg/ml, significantly less (p < 0.005) than in all the lung-transplanted groups. Endothelin in BAL fluid thus was increased after lung transplantation, and still further during rejection.

The true extent of ulcerative colitis? A radiological, endoscopic and histological study

Twenty‐six radiological, endoscopic and histological examinations of the large bowel were performed in 25 patients with ulcerative colitis. Extensive colitis was observed in 42% of the radiological, in 38% of the endoscopic, and in 27% of the histological examinations. Agreement as to the extent of the colitis between all three examination methods was reached in 53% of the cases. The endoscopic extent of colitis varied between left‐sided and extensive in 41% of the patients during a 7‐year median follow‐up. The frequent change in the extent of ulcerative colitis and the considerable disagreement between radiography, colonoscopy and histology in evaluating the extent of colitis justify the question, “Does a true, unambiguous extent of colitis really exist?” It is more likely that the extent of colitis is just a function of time and the examination method used.

Obliterative lesions in small airways in an immunosuppressed porcine heterotopic bronchial allograft model

Abstract We have recently developed a heterotopic large‐animal model for research into obliterative lesions in small airways caused by allograft rejection. In this model, the small airways of subcutaneously implanted allografts gradually obliterate, whereas autografts remain patent. Twenty lung fragments and 20 segments of bronchi were implanted in domestic pigs weighing 20 kg from non‐related donors. The histology of five animals receiving daily cyclosporine A (CsA) (10 mg/kg), azathioprine (2 mg/kg) and methylprednisolone (20 mg), Group C, was compared with that of six animals without immunosuppression, Group A. Four animals received monotherapy with CsA (10 mg/kg) or methylprednisolone (3 mg/kg). The histological findings were graded from 0 to 3 on the basis of implants harvested repeatedly over 3 months. Epithelial destruction and bronchial obliteration was rapid and permanent in all the allografts. Inflammation and fibrosis of the bronchial wall was less prominent in Group C than in Group A and the onset of fibrosis was delayed. Cartilage degeneration and pericartilagineous inflammation were significantly less severe in Group C (P < 0.05). Monotherapy was less potent than triple therapy. This large‐animal model is useful for studying the effects of immunosuppressive drugs on obliterative airway disease.

Obliterative airway disease in a porcine heterotopic bronchial allograft model

Abstract Representative animal models are needed for the study of posttransplant obliterative bronchiolitis (OB). Because human OB originates in terminal bronchi, the validity of tracheal models can be questioned. Using our hetrotopic model, we implanted pieces of a lobar bronchus subcutaneously into domestic pigs. Five groups were included: autograft implants, allograft implants, allograft implants with 2 regimens of cyclosporine (CsA)‐azathioprine (AZA)‐methylprednisolone (MP), and allograft implants with CsA‐SDZ RAD‐MP. Samples were harvested at 2 weeks and at 1, 2, and 3 months. The histological findings were graded from 0 to 3. Following initial ischemic epithelial damage, autograft implants recovered, but untreated allografts and those treated with CsA‐AZA‐MP were totally and permanently damaged within one month. In the group treated with CsA‐SDZ RAD‐MP, a maximal grade 1.5 ± 0.5 epithelial injury was seen at one month. Epithelial damage preceded and correlated with luminal obliteration. The obliterative lesions histologically resembled human OB. Differences from our previous findings with terminal bronchioles were minor. This study supports the use of larger‐size airways in the study of OB.

Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon-α

The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation-induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future.