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Biomedical subjects

H Ekberg

Publications and source records attributed to H Ekberg.

At least 55 records · Page 3Linked to original sources
PubMed1997

Single dose anti-CD4 monoclonal antibody for induction of tolerance to cardiac allograft in high- and low-responder rat strain combinations.

Repeated administration of monoclonal antibodies (mAb) directed against the CD4 lymphocyte receptor may induce specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression. We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb (OX-38) on allograft survival in high- and low-responder rat strain combinations. Isogenic strains of DA (RT1av1), PVG (RT1c), AUG (RT1c), and WF (RT1u) rats were used. Recipients in antibody treated groups were given one dose of 5 mg/kg OX-38 mAb on the day of transplant, a dose which was shown to effectively deplete (or block) circulating CD4+ T cells. Other groups were treated for 10 days with cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first compound able to fully eliminate the effect of CsA in the rat cardiac allograft model. The DA strain was identified as a low-responder to the allogeneic haplotype RT1c (PVG or AUG), but not to RT1u (WF), and developed true tolerance following RT1c grafting and OX-38 or low-dose CsA (5 mg/kg) induction, as verified by the response to retransplantation of a graft from the same donor strain or a third-party challenge. PVG recipients of DA grafts were characterized by high response and only modest (OX-38; median 9.5 days) or moderate (CsA; 23.5 days) prolongation of graft survival. Contrasting graft survival results were obtained in the low-responder combination, either very early rejection (at 10 days) or permanent graft survival (> 100 days). Linomide challenge affected CsA treatment in the high-responder combination but not tolerance induction in the low-responder combination, or the effect of OX-38. It was concluded that in rat heart transplantation a single-dose anti-CD4 mAb therapy may induce permanent donor-specific unresponsiveness in a low-responder strain combination, and that anti-CD4 mAb seems to be unique among immunosuppressive agents while being resistent to challenge by Linomide.

Adjuvants, Immunologic↗
PubMed1997

Mycophenolate mofetil, azathioprine and cyclophosphamide enhanced efficacy combined with cyclosporine in rat cardiac transplantation.

Anti-proliferative drugs have been used for immunosuppression since the introduction of clinical transplantation. Most transplant centres include azathioprine (Aza) and cyclosporine (CyA) in their standard regimens, despite several controlled studies having failed to confirm the benefit of this combination. Aza is still the most commonly used anti-proliferative drug, although no major differences in immunosuppressive or toxic effects have been shown between Aza and cyclophosphamide (Cph). Cph as an adjunct to CyA has never been tested in a randomized study. Recently, mycophenolate mofetil (MMF) has been developed as the most selective inhibitor of T- and B-cell proliferation and promoted as an adjunct to CyA treatment. In the present study, the additive or synergistic effects of these three anti-proliferative agents in combined treatment with CyA have been investigated using a rat cardiac transplantation model in which the immunomodulator linomide (Lin) was included as a potentiator of rejection. As single drug treatment, CyA, Cph and MMF, but not Aza, exerted a beneficial effect on graft survival. This prolongation of graft survival was abrogated when any one drug was administered together with Lin. The addition of MMF, Aza or Cph to CyA plus Lin treatment improved the graft survival significantly, thus demonstrating each of the anti-proliferative drugs to exert additive or synergistic effects in conjunction with cyclosporine. MMF seemed to be the most effective and least toxic of the drugs tested.

Adjuvants, Immunologic↗
PubMed1996

The effect of venous drainage on glucose homeostasis after experimental pancreas transplantation.

In this canine study, glucose homeostasis after clinical pancreas transplantation is complex, with the relative effect of systemic versus portal delivery of insulin remaining unresolved. Thirty-two pancreatectomized dogs received either systemic venous drainage (SVD) with bladder exocrine drainage (n = 16), or portal venous drainage (PVD) with gastric exocrine drainage (n = 16). Cyclosporine (CsA) based immunosuppression was commenced on day -7. The effect of immunosuppression was a significant increase in fasting blood glucose (FBGL) (P = 0.002), fasting insulin (P = 0.024), AUC for insulin (P = 0.009), and K values decreased (P = 0.009). FBGL and K values remained abnormal after transplantation with no significant difference seen between SVD and PVD. However, fasting insulin became significantly lower after PVD and AUC insulin fell in both groups. CsA levels fell in both groups after transplantation, mirroring the fall in AUC insulin, and implicating CsA as a major cause of peripheral resistance to insulin. In conclusion, PVD did not demonstrate a significant advantage over SVD in handling an intravenous glucose challenge. The need for pancreatectomy in large animals may make them an unsatisfactory experimental model to evaluate the glucoregulatory effects of pancreas allotransplantation.

Animals↗
PubMed1996

Experimental hyperacute rejection in pancreas allotransplants.

A model of sensitization by intraperitoneal lymph node inoculation was developed to test the hypothesis that hyperacute rejection (HAR) could occur in sensitized recipients of vascularized pancreas allografts. Ten pairs of outbred mongrel dogs that were lymphocytotoxic cross-match assay negative were inoculated with homogenized lymph nodes on either three or four occasions at fortnightly intervals before renal transplantation. A renal allograft from the same donor was used to test the HAR response and to further enhance sensitization by rejection of a vascularized organ. Pancreas transplants were performed 2 weeks later, with biopsies of the graft and blood samples taken at 0, 10, 20, and 30 min and then at 30-min intervals until the grafts were no longer viable. All renal and pancreas grafts were rejected in a classical hyperacute pattern. Within 4 min of revascularization of the pancreas, central lobular hemorrhage and vascular congestion appeared, followed by general edema. Histology demonstrated parallel changes of edema, vascular congestion, necrosis, hemorrhage, and leukocytic infiltrate, which all preceded graft infarction. A sharp decline in both arterial and venous white blood cell count and platelets occurred within 10 min of revascularization with initial sequestration and subsequent release of platelets from the graft (P=0.02). In summary, HAR of the allografted pancreas can be observed by the surgeon within minutes of revascularization, with predictable macroscopic and microscopic changes. This study supports the use of routine lymphocytotoxic cross-match tests for all recipients of pancreas transplants and implies that particular care is warranted in regraft pancreas allograft recipients.

Acute Disease↗
PubMed1996

Similar treatment success rate after renal transplantation in diabetic and nondiabetic patients due to improved short- and long-term diabetic patient survival.

In the early era of transplantation, it was common practice to exclude diabetic patients since the outcome in such cases was usually poor. At our center in Malmö, Sweden, diabetic nephropathy was never regarded as a contraindication. During the 22-year period from 1972 to 1993, 223 renal allografts were transplanted in 189 uremic diabetics, representing 24% of all renal transplant recipients (n = 788). The two subgroups - patients with and without diabetes - did not differ significantly in graft survival rates for the 22-year period, which was characterized by a successive improvement in the success rate that was especially striking in the diabetic nephropathy subgroup. Among transplantations performed before 1988, the overall patient survival rate was significantly lower in the diabetic subgroup than in the remainder. After 1988 (when a series of new procedures had been adopted), the patient survival rate in the diabetic subgroup was similar to that in the nondiabetic subgroup, a similarity that persisted for at least 5 years. The 1st year post-transplant mortality rate was reduced in diabetic patients from 24% before 1988 to 0% in those transplanted after 1988. In the 22-year period as a whole, cardiovascular or cerebrovascular events were the most common cause of death in both subgroups; the risk of cardiovascular or cerebrovascular death was reduced after 1988, and the rates were similar in both subgroups. The improved success rate of renal transplantation in patients with diabetic nephropathy supports continuation of the renal transplant program, which is based on careful management of the early stages of the disease.

Adult↗
PubMed1996

Impaired renal artery blood flow at transplantation is correlated to delayed onset of graft function.

The aim of this prospective study was to evaluate a transit time flowmeter (Transonic, USA) in renal transplantation with respect to feasibility and estimation of graft circulation. Subsequently, the measurements were evaluated for their ability to predict delayed onset of function, occurrence of acute rejection or graft loss within 3 months after transplantation. Renal artery blood flow was measured and resistance calculated in 100 transplants-62 cadaveric donor (CD) and 38 living donor (LD)-immediately after restoration of graft circulation and before wound closure. Low blood flow (< 250 ml/min) and high resistance (> 392 mPRU) correlated positively with a long cold ischemia time and delayed onset of graft function, including the need for post-transplant dialysis. No correlation with rejection or graft loss was found. Blood flow measurements with the transit time flowmeter were easy to perform and immediate estimation of transplant circulation was achieved. Transplants at risk for delayed onset of function were identified.

Adult↗
PubMed1996

Thalidomide prolonged graft survival in a rat cardiac transplant model but had no inhibitory effect on lymphocyte function in vitro.

The effects of thalidomide on in vitro interleukin 2 (IL-2) production and thymidine uptake by human peripheral blood lymphocytes or rat splenocytes were investigated. Phytohaemagglutinin-stimulated human lymphocytes were incubated in the presence of thalidomide added at culture initiation. No immunosuppressive effect of thalidomide was observed in these experiments. Primary human mixed lymphocyte cultures treated with thalidomide for 6 days were also unaffected. A microsomal rabbit liver homogenate was prepared for metabolizing thalidomide. Stimulated lymphocytes secreted significantly more IL-2 in the presence of microsomal-treated thalidomide than did controls. The effect of thalidomide was then studied either as single therapy or in combination with cyclosporin A (CyA) in a rat allograft cardiac transplantation model. In addition, T cell subsets were analysed by flow cytometry in untransplanted rats treated with thalidomide. Treatment was given as induction therapy from the day of transplantation until day 9. Graft survival in rats treated with thalidomide was significantly prolonged compared to the untreated group. No difference in graft survival was detected between rats treated with thalidomide or CyA only. Graft survival was found to be slightly prolonged in rats given thalidomide and CyA in combination compared to rats treated with CyA alone. In untransplanted rats given thalidomide a decrease of CD4 positive T cells was detected on days 3 and 5. The T helper/cytotoxic-suppressor cell ratio was significantly diminished but, after 1 week of treatment, values for T cell subsets had almost returned to baseline levels. No inhibitory effect was obtained when phytohaemagglutinin-stimulated rat splenocytes were cultured with metabolized thalidomide. In summary, the ability of thalidomide to improve allograft survival in a solid organ transplant model was verified. The occurrence of thalidomide-induced changes in T cell subset ratios was demonstrated. In in vitro studies, however, there was no decrease but an increase in IL-2 production, and no change in thymidine uptake. The mechanism responsible for the immunosuppressive effect of thalidomide remains to be elucidated.

Animals↗
PubMed1996

Moderate additive immunosuppressive effect of thalidomide combined with cyclosporin A in rat cardiac transplantation.

Thalidomide is an immunomodulating agent shown to prolong graft survival in experimental skin, renal, cardiac and bone marrow transplantation. The main purpose of the present study was to investigate the possible additive effect of combining thalidomide with cyclosporin A (CyA). Members of our group have previously created a basis for such studies by demonstrating the ability of Linomide to abolish the effect of CyA. The additional effect of combined treatment with a second drug is thereby more readily evaluated, compared with using subtherapeutic dose levels to induce early rejection. Cardiac grafting was performed in three rat strain combinations (BN to WF, DA to Lew, and BN to Lew). Rats were given no treatment, or thalidomide, CyA and/or Linomide in single, double or triple drug therapy. Except for a consistent beneficial effect of CyA as single drug treatment, graft survival varied depending on the rat strain combination used. In the DA to Lew combination, the expected effects of Linomide were seen, and thalidomide was shown to prolong graft survival significantly (P = 0.004) when added to CyA and Linomide. However, there was no effect of thalidomide when given alone. In WF recipients of BN hearts, thalidomide tended to prolong graft survival (P = 0.07), and surprisingly Linomide manifested a marked immunosuppressive effect (P = 0.0002) and did not counteract the effect of CyA. When transplanting BN grafts to Lew recipients, Linomide reduced significantly but did not abolish completely the effect of CyA. Neither Linomide nor thalidomide had any beneficial impact on graft survival on their own. To sum up, thalidomide was shown to have a minimal or moderate immunosuppressive effect additive to that of CyA. The effects of the two immunomodulating drugs, thalidomide and Linomide, varied depending on the rat strain combination used, and were similar with respect to prolongation of graft survival when used as single drug treatment in BN to WF grafting, a fact which may indicate them to have a similar mechanism of action, both having been shown to exert similar effects on levels of tumour necrosis factor alpha.

Adjuvants, Immunologic↗
PubMed1996

Bioavailability of cyclosporine in rats after intragastric administration: a comparative study of the L2-phase and two other lipid-based vehicles.

The purpose of this study was to evaluate formulations based on surface active dietary lipids only as oral vehicles for cyclosporine. The absolute bioavailability of cyclosporine from two new lipid vehicles was determined in rats after intragastric administration and compared to that of Sandimmun oral solution, which contains non-ionic surface active substances in addition to dietary lipids. In the new vehicles, cyclosporine was dissolved in two different mixtures of glycerides from long-chained fatty acids. One mixture forms an L2-phase, an oil with very low interfacial tension towards water, and was administered both as the oily L2-phase and as a predispersed emulsion formulation. The other mixture forms a liquid crystalline phase and was administered only as an aqueous dispersion. The mean bioavailability of cyclosporine from Sandimmun was 8% while it was 34% from the L2-phase, 38% from the predispersed L2-phase and 27% from the dispersed liquid crystalline phase. The coefficients of variation in area under the blood concentration curve after administration of the two formulations based on the L2-phase were quite low (31% for the L2-phase and 24% for the predispersed L2-phase) and comparable to that after intravenous administration (24%), while the dispersed liquid crystalline phase gave a higher variability (91%), comparable to that of Sandimmun oral solution (101%). The low variabilities found with the two L2-phase vehicles suggest that this formulation is "self-emulsifying' in the gastrointestinal tract. Since the L2-phase is based on dietary lipids only, it is expected to be well tolerated and could prove to be a good vehicle for long-term clinical use of oral cyclosporine.

Administration, Oral↗
PubMed1995

Enhancement of the immunosuppressive effect of cyclosporin A by ciprofloxacin in a rat cardiac allograft transplantation model.

Ciprofloxacin hyperinduces interleukin-2 production in stimulated human and mouse lymphocytes. In this study, an enhanced and prolonged interleukin-2 response was also detected in polyclonally stimulated rat splenocytes in the presence of ciprofloxacin (5-80 micrograms/ml) compared to control cells without any antibiotic. Ciprofloxacin was able to counteract the immunosuppressive effect of 10 ng/ml cyclosporin A (CyA) but did not interfere with higher CyA concentrations. In parallel, ciprofloxacin did not influence thymidine uptake in mixed lymphocyte reactions in the presence of CyA. To obtain an in vivo application of these findings, graft survival was studied by performing rat cardiac allograft transplantations in the presence or absence of CyA. Brown Norway rats served as donors and Wistar Furth rats as recipients. Ciprofloxacin was injected intraperitoneally either at a high-dose regimen (240 mg/kg per 24 h) into rats every 8th h starting 1 day before transplantation until day 21 or graft loss, or it was injected at a low and clinically relevant dose regimen (45 mg/kg per 24 h) until day 9. CyA was administered orally (10 mg/kg per 24 h) from day 1 through day 9. Ciprofloxacin given alone at a high-dose regimen resulted in a median graft survival of 14.8 days, which was significantly longer than graft survival in rats without treatment (median 8.0 days). A low-dose regimen of ciprofloxacin alone did not affect graft survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Follow-up after curative surgery for colorectal carcinoma. Randomized comparison with no follow-up.

PURPOSE: This study investigated the value of intense follow-up compared with no follow-up after curative surgery of cancer in the colon or rectum. METHODS: One hundred seven patients were randomized to no follow-up (control group; n = 54) or intense follow-up (follow-up group; n = 53) after surgery and early postoperative colonoscopy. Patients in the follow-up group were followed at frequent intervals with clinical examination, rigid proctosigmoidoscopy, colonoscopy, computed tomography of the pelvis (in patients operated with abdominoperineal resection), pulmonary x-ray, liver function tests, and determinations of carcinoembryonic antigen and fecal hemoglobin. Follow-up ranged from 5.5 to 8.8 years after primary surgery. RESULTS: Tumor recurred in 18 patients (33 percent) in the control group and in 17 patients (32 percent) in the follow-up group. Reresection with curative intent was performed in three patients in the control group and in five patients (four of whom were asymptomatic) in the follow-up group. In the follow-up group two asymptomatic patients with elevated carcinoembryonic antigen levels were disease-free three and five and one-half years after reresection and were the only patients apparently cured by reresection. No patient underwent surgery for metastatic disease in the liver or lungs. Symptomatic metachronous carcinoma was detected in one patient (control group) after three years. Five-year survival rate was 67 percent in the control group and 75 percent in the follow-up group (P > 0.05); the corresponding cancer-specific survival rates were 71 percent and 78 percent, respectively. CONCLUSION: Intense follow-up after resection of colorectal cancer did not prolong survival in this study.

Aged↗