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The prevention of diabetes by the immunomodulatory agent FTY720 (fingolimod) was studied in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Immune cell subtypes and cytokine profiles in pancreatic islets, secondary lymphoid tissue, and serum were analyzed for signs of immune cell activation. Animals were treated with FTY720 (1 mg/kg body weight) for 40 d starting on d 50 of life. Changes in gene and protein expression of cytokines, CD8 markers, monocyte chemoattractant protein-1, inducible NO synthase, and caspase 3 were evaluated. Treatment with FTY720 prevented diabetes manifestation and islet infiltration around d 60 of life, the usual time of spontaneous diabetes development. On d 120, 30 d after the end of FTY720 therapy, diabetes prevention persisted. However, six of 12 treated animals showed increased gene expression of IL-1β, TNF-α, and CD8 markers in pancreas-draining lymph nodes, indicating immune cell activation. In parallel, serum concentrations of these proinflammatory cytokines were increased. These six animals also showed macrophage infiltration without proinflammatory cytokine expression in a small minority (2–3%) of islets. Interestingly, regulatory T lymphocytes were significantly increased in the efferent vessels of the pancreas-draining lymph nodes only in animals without signs of immune cell activation but not in the rats with immune cell activation. This provides an indication for a lack of protective capacity in the animals with activated immune cells. Thus, FTY720 treatment prevented the manifestation of diabetes by promoting the retention of activated immune cells in the lymph nodes, thereby avoiding islet infiltration and β-cell destruction by proinflammatory cytokines.

Cavernous hemangiomas are the most common benign tumors of the liver. They can reach enormous sizes and cause various complications. Kasabach-Merritt syndrome is a rare but serious complication characterized by consumptive coagulopathy caused by the hemangioma; mortality rate ranges between 10 and 37%. More than 80% of cases occur within the first year of life. Goals of the treatment are to control the coagulopathyand thrombocytopenia as well as to eradicate the hemangioma. Different nonsurgical treatment regimens are performed, includingsystemic corticosteroids, irradiation and various chemicals. Surgery should be limited to symptomatic or complicated cases. Although difficult, resection of the tumor is usually curative. Here we present a 44-year-old woman with giant hepatic hemangioma causing Kasabach-Merritt syndrome managed by enucleation.

With continuously rising survival rates following renal transplantation, health-related quality of life (HQOL) of long-term transplant survivors becomes increasingly important.Recipients more than 15 years after successful renal transplantation were studied retrospectively. HQOL in 139 long-term transplant recipients was assessed using the SF-36 and the disease-specific kidney transplant questionnaire (KTQ-25).Long-term transplant recipients revealed satisfactory HQOL that was comparable to the healthy population in four of eight SF-36 categories (role physical, social functioning, role emotional and mental health). Other SF-36 categories such as physical functioning, physical pain, general health, and vitality were reduced. Among the study population, disease-specific HQOL was comparable or even improved to that of patients awaiting transplantation. In contrast to retired or unemployed patients, employed recipients revealed a highly significant improved HQOL in numerous SF-36 categories such as physical functioning (P0.001), physical pain (P0.001), general health (P0.001), vitality (P0.001), social functioning (P0.005), and mental health (P0.001), as well as for the KTQ-dimensions physical symptoms (P0.001), fatigue (P0.001), uncertainty/fear (P0.01), and emotions (P0.05). Other factors positively correlating with improved HQOL in certain dimensions were living situation, systolic blood pressure, and recipient age.More than 15 years after renal transplantation, recipients present satisfactory HQOL comparable to the general healthy population or at least to pretransplant patients. Vocational rehabilitation following renal transplantation is of highest importance among long-term survivors and is associated with improved HQOL.

The uremic state in patients with terminal renal insufficiency is accompanied by a bleeding tendency connected with platelet dysfunction. Prolonged cold ischemia and inflammatory interactions between leukocytes, platelets and endothelial cells contribute to ischemia-/reperfusion (I/R) injury and may impair long-term graft survival. We evaluated the influence of the duration of cold preservation time on the expression of platelet GPIIb/IIIa and P-selectin and on the formation of leukocyte-platelet complexes after kidney transplantation. Fourteen patients undergoing kidney transplantation were divided into group I with long preservation time (26.6 +/- 1.9 h) and group II with short preservation time (8 +/- 6.1 h). Five venous blood samples (3 ml) were taken before induction of anesthesia, 12 h, 2, 7 and 14 d after transplantation. Surface expression of the GPIIb/IIIa, P-selectin and the percentage of platelet-granulocyte complexes were quantified by flow cytometry. Additionally blood from seven healthy volunteers was analyzed. GPIIb/IIIa and P-selectin expression on circulating platelets were significantly decreased in the long and the short-term graft preservation group compared with healthy volunteers. A significantly reduced P-selectin expression was found in the long-term preservation group compared with the short-term group. The percentage of platelet-granulocyte complexes also decreased in both preservation groups in the first 2 d after reperfusion and remained in this state in the long-term preservation group. Reduced expression of P-selectin on circulating platelets may be an indicator of I/R injury after prolonged kidney graft preservation.

The therapeutic capacity of an antibody directed against the T cell receptor (anti-TCR) of the TCR/CD3 complex alone or in combination with fingolimod (FTY720) to reverse the diabetic metabolic state through suppression of autoimmunity and stimulation of β cell regeneration was analyzed in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Animals were treated with anti-TCR (0.5 mg/kg body weight for 5 days) monotherapy or in combination with fingolimod (1 mg/kg body weight for 40 days). Metabolic changes and β cell morphology were analyzed before, immediately after, and 60 days after end of therapy. Both therapies were started early after disease manifestation and led to normoglycemia in parallel with an increase of the C-peptide concentration. Combination therapy increased the β cell mass reaching a range of normoglycemic controls, decreased the apoptosis rate fivefold, and increased the proliferation rate threefold. Additionally, at 60 days after therapy, islets were virtually free of T cells, macrophages, and cytokine expression. In contrast, after anti-TCR monotherapy, β cell mass remained low with an activated immune cell infiltrate. A concomitant fivefold increased β cell apoptosis rate resulted in a complete loss of β cells. Only combination therapy yielded sustained normoglycemia with full reversal of islet infiltration and restoration of pancreatic β cell mass.Combination therapy of anti-TCR and fingolimod was effective in the reversal of T1D. Combination therapy increased the pancreatic β cell mass to normoglycemic control levels. Combination therapy leads to a full reversal of pancreatic islet infiltration. Anti-TCR monotherapy did not abolish islet infiltration. Combination therapy was successful only immediately after diabetes manifestation.

Liver xenografts transplanted from guinea pig to rat suffer from inadequate organ reperfusion and initial dysfunction, despite sufficient complement depletion using cobra venom factor (CVF). Reperfusion injury is prevented when complement depleted donors are treated with the prostacyclin analog epoprostenol. Histological analysis suggests that epoprostenol preconditioning prevents post-reperfusion spasms of the intrahepatic branches of the portal vein and strongly reduces appearance of hepatocyte apoptosis shortly after transplantation. Cobra-venom-treated rats show breakdown of glucose metabolism and die in acute hypoglycaemia, whereas the additional application of epoprostenol restores gluconeogenesis. Consequently, recipient survival after epoprostenol and CVF treatment is significantly improved compared with animals receiving CVF only (5.1 +/- 2.6 h vs. 17.9 +/- 5.1 h). These data demonstrate that initial dysfunction of discordant liver grafts in the guinea-pig-to-rat species combination, can be overcome by the application of epoprostenol combined with CVF. Using this pharmacologic regimen, the discordant guinea-pig-to-rat model appears useful to study further questions concerning functional and immunological compatibility of a discordant liver xenograft.

Asthma is a major cause of morbidity worldwide with prevalence and severity still increasing at an alarming pace. Hallmarks of this disease include early-phase bronchoconstriction with subsequent eosinophil infiltration, symptoms that may be mimicked in vivo by the complement-derived C3a anaphylatoxin, following its interaction with the single-copy C3aR. We analyzed the pathophysiological role of the C3a anaphylatoxin in a model of experimental OVA-induced allergic asthma, using an inbred guinea pig strain phenotypically unresponsive to C3a. Molecular analysis of this defect revealed a point mutation within the coding region of the C3aR that creates a stop codon, thereby effectively inactivating gene function. When challenged by OVA inhalation, sensitized animals of this strain exhibited a bronchoconstriction decreased by ∼30% in comparison to the corresponding wild-type strain. These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.

BACKGROUND Ischemia/reperfusion (I/R) injury after pancreas transplantation might result in graft pancreatitis. The role of heme oxygenase-1 (HO-1) in pancreas transplantation and prevention of graft pancreatitis is unknown. METHOD We studied the impact of HO-1 induction with cobalt protoporphyrin (CoPP) in experimental pancreas transplantation with moderate (6 hr) and prolonged (20 hr) cold ischemic time (CIT). Donor animals received CoPP 5 mg/kg intraperitoneal at 48 hr or intraperitoneal saline injections in the corresponding control groups before procurement. Harvested grafts were perfused with HTK solution and stored at 4 degrees C. RESULTS After prolonged CIT, graft survival was 100% with CoPP pretreatment in contrast to only 37.5% without pretreatment. CoPP-pretreated grafts demonstrated an unimpaired endocrine graft function at moderate and prolonged CIT. Serum lipase activity as a sign of exocrine preservation was significantly lower. In addition, morphological architecture was well preserved. CoPP pretreatment markedly increased HO-1 gene expression in donor pancreas (130-fold increase) by means of quantitative reverse transcriptase -polymerase chain reaction. Immunohistochemical examinations showed that the increase of HO-1 on the protein level was related to HO-1-positive donor macrophages in the pancreas grafts. HO-1 overexpression was accompanied by significant decrease of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-2, IL-6, interferon-y, and by significant increase of the anti-inflammatory cytokine IL-10 and less expression of adhesion molecules such as e- and p-selectins. CONCLUSIONS HO-1 is highly inducible in the allograft rat pancreas and associated with a survival benefit and good graft function after transplantation. This study contributes to the beneficial potentials of HO-1 for the prevention of graft pancreatitis.

Background Currently, many centers perform laparoscopic donor nephrectomy (DN). We studied the outcome of donors and recipients following open DN using either flank incision (ODN) or mini-incision (MIDN). Methods Data of 196 living kidney donors were recorded prospectively. In 127 cases ODN and 69 cases MIDN were performed. Results Demographic details of donors were comparable for both groups. The left kidney was procured in 58% for ODN and in 64% for MIDN. Multiple arteries were more frequently present when MIDN (11% vs. 28%) was performed. The mean operating time was 129 min for ODN and 133 min for MIDN. Early complications occurred in 7% following ODN and in 4% following MIDN. Late complications were observed in 21% after ODN and 1% after MIDN. The mean hospital stay was significantly longer following ODN compared with MIDN (7.5 vs. 6.4 days). The primary graft function rate was 97% in both groups. One-year graft survival was 97% after ODN and 100% after MIDN. Conclusions Results following MIDN are superior to those following ODN. Even in case of multiple renal vessels MIDN can be safely applied. In comparison with laparoscopic DN advantages of MIDN may be reduced costs, shorter operating time, and comparable cosmetic results.

Platelet dysfunction contributes to haemostatic defects, possibly leading to bleeding complications. We hypothesised that liver transplantation and liver resection, together with portal clamping time, might be a potential stimulus for platelet activation. Therefore, we determined the expression of platelet GPIIb/IIIa and P-selectin, representing important platelet activation markers, and the thrombopoietin (TPO) serum level after transplantation and resection. Twenty patients [ten that had undergone orthotopic liver transplantation (OLT), ten with liver resection (LRX)] were included in the study. From sequential venous blood samples, surface expression of GPIIb/IIIa and P-selectin was quantified by flow cytometry, and TPO serum levels were determined by ELISA. Baseline GPIIb/IIIa receptor expression on circulating platelets was significantly reduced in the OLT group compared to the LRX group and healthy volunteers. GPIIb/IIIa expression after activation with TRAP-6 increased significantly ( P