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Biomedical subjects

C G Groth

Publications and source records attributed to C G Groth.

At least 37 records · Page 2Linked to original sources
PubMed2000

Lack of antibody production against Hanganutziu-Deicher (H-D) antigens with N-glycolylneuraminic acid in patients with porcine exposure history.

The significance of non-alphagalactosyl antigens remains unclear in pig-to-primate xenotransplantation. Hanganutziu-Deicher (H-D) antigens with terminal N-glycolylneuraminic acid (NeuGc) are widely expressed on endothelial cells of mammalian species, with the exception of humans. As baboons and monkeys also express H-D antigens, a pig-to-non-human primate experimental model cannot resolve the question of whether H-D antigens can elicit a potent humoral response in human recipients. The purpose of this study was to elucidate the clinical significance of H-D antigens by examining the sera from patients who have been previously exposed to porcine tissue. After the digestion of porcine aortic endothelial cells (PAEC) by neuraminidase, NeuGc and N-acetylneuraminic acid (NeuAc) were quantitated by HPLC. IgG and IgM antibody levels against H-D antigens were measured by NeuGc-GM3-coated ELISA plates in the sera of patients who had undergone ex vivo kidney perfusion 1 to 3 weeks and 2 years previously (n=2) or had been injected with fetal porcine islets 2 months previously (n= 10). HPLC determined that 9.7x 10(7) NeuAc and 6.3x 10(7) NeuGc residues per cell were released from PAEC by neuraminidase, while 25.7x 10(7) NeuAc and an undetectable level of NeuGc were released from human aortic endothelial cells (HAEC). No significant elevation of IgG or IgM antibody levels against NeuGc-GM3 was observed in sera from patients with a history of porcine exposure. Considering the active production of antibody against the foreign galactosyl antigens after pig-to-human xenotransplantation, some production of antibodies against the equally foreign H-D antigens would be expected, because large amounts of NeuGc terminated saccharides are present in the pig endothelial cell surface. However, no production of antibodies directed to H-D antigens could be found in patients exposed to porcine tissue. Further studies are warranted to explain why H-D antigens do not elicit a significant antibody production.

Animals↗
PubMed2000

Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers.

A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration-time curve increased proportionally with dose. Mean (+/- SD) whole blood terminal disposition half-life (t1/2), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 +/- 12 hours, 278 +/- 117 mL/h x kg and 23 +/- 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers.

Administration, Oral↗
PubMed2000

Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes.

Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated inflammatory reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.

Blood Coagulation↗
PubMed1999

Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.

BACKGROUND: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS: At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Adult↗
PubMed1999

Fetal porcine islet-like cell clusters transplanted to cynomolgus monkeys: an immunohistochemical study.

BACKGROUND: The mechanism(s) involved in acute cellular xenograft rejection have hitherto been generated in vitro or in different experimental models, with pig tissue being transplanted to rodents. There is an urgent need to validate these results in a clinically more relevant combination of species. METHODS: Fetal porcine islet-like cell clusters (ICC) were transplanted under the kidney capsule in cynomolgus monkeys, either untreated or given immunosuppression with cyclosporine (CsA; 10 mg/kg body weight, intramuscularly) and 15-deoxyspergualin (DSG; 5 mg/kg body weight, intramuscularly). ICC xenografts were examined at 1, 3, 6, or 10-12 days after transplantation, using immunohistochemical techniques. Serum levels of xenoreactive antibodies were measured with ELISA. RESULTS: No deposits of IgM, IgG, Clq, or C3 were detected within the ICC xenograft in any of the monkeys. Likewise, no significant increase in the levels of xenoreactive antibodies were found after transplantation. In untreated animals, a few N-Elastase-positive cells (neutrophil granulocytes) were seen in the xenograft at day 1. A few mononuclear cells were present in the adjacent renal parenchyma, but they did not infiltrate the xenograft. At this time (day 1), early signs of necrosis were observed in the central parts of the graft. On day 3, the graft had a large, central necrotic area that contained polymorphonuclear cells; the remaining parts of the xenograft showed severe infiltration with CD8+ T cells. Occasional CD68+ cells (macrophages) were seen on days 1 and 3. On day 6, large numbers of macrophages were found infiltrating the entire graft. A few CD20+ B cells, accumulated as small clusters, were also found. Only a few natural killer cells (CD56+) were detected. The CsA/DSG-treated monkeys showed markedly fewer CD2+/CD8+ T cells on day 6 than the untreated monkeys, and the ICC graft was clearly better preserved. However, the number of CD8+ and CD68+ cells had increased considerably at 12 days after transplantation and diffusely infiltrated the whole ICC xenograft. CONCLUSION: Porcine ICC transplanted under the kidney capsule in cynomolgus monkeys were rejected by an acute cell-mediated rejection progressing during the first 6 days after transplantation. The process was not dependent on host Ig or C3 binding to the graft. Although the rejection of porcine ICC was significantly delayed in CsA/DSG-treated monkeys, the ICC xenografts were almost completely destroyed 12 days after transplantation.

Animals↗
PubMed1999

Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation.

BACKGROUND: The purpose of pancreatic transplantation in insulin-dependent diabetic patients is to restore normoglycemia and thereby prevent the secondary complications of diabetes. However, uncertainty remains as to whether the mortality rate in diabetic patients can be affected by this procedure. METHOD: We followed 14 patients with insulin-dependent diabetes mellitus (IDDM) and end-stage diabetic nephropathy for 10 years after successful combined kidney and pancreas transplantation. Fifteen diabetic patients subjected to kidney transplantation alone have served as controls. The glycemic control has been studied annually for 10 years and diabetic polyneuropathy has been assessed in both groups after 2, 4, and 8 years. RESULTS: In recipients of pancreas-kidney grafts, metabolic control was maintained throughout the observation period, with values of glycated hemoglobin in the normal range. In contrast, glucose metabolism was impaired in the control group, with glycated hemoglobin values around 10%. Nerve conduction and parasympathetic autonomic dysfunction improved in both groups after 2 years; there was no difference between the groups. After 4 years, we found a significant difference between the study group and the control group, and after 8 years it had widened. At the 4-year evaluation, there was no difference in mortality between the groups. At 8 years, however, a significant difference was noted, which was further substantiated at 10 years with a 20% mortality rate in the pancreas-kidney group versus an 80% mortality in the kidney alone group. CONCLUSIONS: We found a substantial reduction in mortality in IDDM patients 10 years after successful combined pancreas and kidney transplantation. We speculate that the decrease in mortality was due to the beneficial effect of long-term normoglycemia on diabetic late complications and suggest therefore that combined pancreas and kidney transplantation, rather than kidney transplantation alone, should be offered to IDDM patients with end-stage diabetic nephropathy.

Adult↗
PubMed1999

Xenoislet transplantation: experimental and clinical aspects.

Ten diabetic renal transplant patients had porcine fetal islet-like cell clusters (ICC) injected intraportally or placed under the kidney capsule. In some patients, temporary graft survival was achieved, as evidenced by the urinary excretion of small amounts of porcine C-peptide (4 patients) and the identification of some intact insulin-staining cells in a biopsy specimen (1 patient). Glucose metabolism remained unaffected. To improve the results, better islets and better immunosuppressive protocols are required. We found that, while fetal porcine ICC produced insulin only after several weeks, adult islets gave immediate insulin production. The search for an optimal immunosuppression was conducted in the pig-to-rat islet transplant model. A clear inhibitory effect on the xenograft rejection was observed when using some of the new drugs. The best results were achieved with a triple drug regimen consisting of cyclosporine, mycophenolate mofetil and leflunomide.

Animals↗
PubMed1999

Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients.

AIMS: To evaluate the relationship between tacrolimus whole blood concentrations and side-effects and rejections in 14 renal transplant recipients. METHODS: Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656). RESULTS: Side-effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml-1, with 41% of concentrations within the interval of 20-30 ng ml-1, with 26% of the concentrations within the interval of 10-20 ng ml-1 and with only 5.3% on the concentrations lower than 10 ng ml-1. No relation to the tacrolimus concentration was seen for rejection episodes. CONCLUSIONS: We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml-1 to avoid side-effects, such as nephro-and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.

Adult↗
PubMed1999

Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation?

The remarkable difference in success rates between clinical pancreas transplantation and islet transplantation is poorly understood. Despite the same histocompatibility barrier and similar immunosuppressive treatments in both transplantation procedures, human intraportal islet transplantation has a much inferior success rate than does vascularized pancreas transplantation. Thus far, little attention has been directed to the possibility that islets transplanted into the blood stream may elicit an injurious incompatibility reaction. We have tested this hypothesis in vitro with human islets and in vivo with porcine islets. Human islets were exposed to nonanticoagulated human ABO-compatible blood in surface-heparinized polyvinyl chloride tubing loops. Heparin and/or the soluble complement receptor 1 (sCR1) TP10 were tested as additives. Adult porcine islets were transplanted intraportally into pigs, and the liver was recovered after 60 min for immunohistochemical staining. Human islets induced a rapid consumption and activation of platelets. Neutrophils and monocytes were also consumed, and the coagulation and complement systems were activated. Upon histological examination, islets were found to be embedded in clots and infiltrated with CD11+ leukocytes. Furthermore, the cellular morphology was disrupted. When heparin and sCR1 were added to the blood, these events were avoided. Porcine islets retrieved in liver biopsies after intraportal islet allotransplantation showed a morphology similar to that of human islets perifused in vitro. Thus, exposure of isolated islets of Langerhans to allogenic blood resulted in significant damage to the islets, a finding that could explain the unsatisfactory clinical results obtained with intraportal islet transplantation. Because administration of heparin in combination with a soluble complement receptor abrogated these events, such treatment would presumably improve the outcome of clinical islet transplantation by reducing both initial islet loss and subsequent specific immune responses.

Adult↗
PubMed1998

No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts.

BACKGROUND: The study of whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for evaluating the safety of pig-to-man xenotransplantation. PERV is carried in the pig germline, and all recipients of porcine tissues or organs will be exposed to the virus. METHODS: We studied 10 diabetic patients who had received porcine fetal islets between 1990 and 1993, looking for evidence of PERV infection by using PCR serology, PCR, and reverse transcriptase assays. Prolonged xenograft survival (up to a year) was confirmed in five patients by porcine C-peptide excretion and detection of pig mitochondrial DNA (mtDNA) in serum. FINDINGS: Despite the evidence for extended exposure to pig cells and despite concomitant immunosuppressive therapy, we were unable to detect markers of PERV infection in any patient. Screening for two PERV sequences in peripheral blood lymphocytes collected 4-7 years after the xenotransplantation was negative. Markers of PERV expression, including viral RNA and reverse transcriptase, were undetectable in sera from both early (day 3 to day 180) and late (4-7 years) time points. Western blot analysis for antibodies was consistently negative. INTERPRETATION: These results suggested the absence of PERV infection in these patients. Also this study establishes a minimum standard for post-transplant surveillance of patients given porcine xenografts.

Adult↗
PubMed1998

[Intestinal transplantation. The first Swedish transplantation of the small intestine in an adult patient with pseudoobstruction].

Recent advances, first and foremost the development of new immunosuppressive agents, have markedly improved the outcome of intestinal transplantation, which is a treatment option for patients with serious intestinal diseases who have become dependent on total parenteral nutrition. The first small bowel transplantation in Sweden was performed at Huddinge Hospital in 1997, in the adult patient with intestinal pseudo-obstruction. The article reports the course of this patient and an update of international progress in intestinal transplantation.

Abdominal Pain↗
PubMed1998

Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin).

BACKGROUND: Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia. METHODS: Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection. RESULTS: In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus. CONCLUSION: It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.

Adrenal Cortex Hormones↗
PubMed1998

[Transplantation of islets of Langerhans in type 1 diabetes. Three cases treated in Sweden to date].

The article consists in a report of the first three cases of human islet transplantation to have been carried out in Sweden. Cadaveric pancreatic glands were harvested and flown to the islet transplantation laboratory at the University of Giessen in Germany. After isolation, the islets were returned to Huddinge Hospital in Stockholm. The recipients were diabetic renal transplant patients, who received 5,000-8,000 islets by intraportal injection. Initially blood glucose levels were stabilised and HbA1c levels normalised, but no patient became insulin independent. After a few months serum C-peptide levels diminished, and after 6-10 months were undetectable. Islet function loss is probably to be explained by rejection and cytomegalvirus infection. In future cases new improved immunosuppressive protocols will be implemented.

Adult↗