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Biomedical subjects

E Kemp

Publications and source records attributed to E Kemp.

At least 19 recordsLinked to original sources
PubMed1992

Sequential, morphological, and antidonor antibody analysis in a hamster-to-rat heart transplantation model.

The pathogenesis and the mechanism of accelerated graft rejection in concordant xenotransplantation are unclear. The histopathological features and kinetics neither fulfill the criteria of classic hyperacute rejection nor resemble an accelerated type of first-set allograft reaction. The aim of this study was to investigate the mechanism of concordant xenograft rejection in relation to the early morphological changes in hamster hearts transplanted to unmodified rat recipients by sequential, immunohistological analysis of grafts, regional lymph nodes, and spleens and to correlate these results to the production of antidonor antibodies, as determined by a flow cytometric assay. Histopathological features were characterized by a gradually increasing myocytolysis with fragmentation and loss of myofilaments. The first slight signs were observed a few hours after transplantation. Later, vascular changes developed, evolving into a leukocytoclastic type of vasculitis, eventually with thrombosis. No significant interstitial lymphocyte infiltration was present, but neutrophilic granulocytes and macrophages appeared. In addition, a distinct increase in B cells in spleens and lymph nodes was noted. Low levels of preformed antidonor antibodies did not increase during the first 48 h; however, significant amounts of species-, but not donor-, specific antibodies were demonstrated at the time of rejection. These data, together with the morphological observations, indicate a primarily humoral xenograft rejection in this model. Minor damage to graft myocytes a few hours after transplantation, progressing to vascular changes within 24-48 h, further suggests that preformed antidonor antibodies directed against endothelial or myocyte determinants may play an initiating role in the pathogenesis of unmodified, concordant xenograft rejection.

Animals↗
PubMed1992

The distal nephron is preferentially infiltrated by inflammatory cells in acute interstitial nephritis.

In acute interstitial nephritis (AIN), mononuclear cells invade the tubules (tubulitis). The segmental localization of tubulitis is not precisely known. To clarify this question, formalin-fixed kidney biopsy specimens from 13 patients with AIN were studied stereologically by identifying cortical tubules with segment-specific markers. The periodic acid-Schiff reaction, peanut lectin, and antibodies against Tamm-Horsfall protein and epidermal cytokeratins all applied to the same section were used to identify the proximal tubules (PTs), distal convoluted tubules, distal straight tubules, and the cortical collecting system (connecting tubules and cortical collecting ducts), respectively. Morphometrically, an estimate of the relative volume of the inflammatory cell infiltrates within each category of tubular segments was obtained. Inflammatory cells were infrequently found in PTs (1.2%) but were frequently localized in distal tubules and the cortical collecting system (7.6%). There was no difference in the amount of the inflammatory cell infiltrate within these segments. Re-examination of an electron microscopic study of AIN carried out in this laboratory revealed that mononuclear cells were rarely seen in convoluted PTs but were frequently observed in straight PTs and all segments distal to them. The observations indicate that it is the distal nephron which is primarily affected by inflammatory cell infiltration in AIN.

Acute Disease↗
PubMed1992

The mersilene covered intraorbital implant.

The most widely used material for covering spherical intraorbital implants is sclera. Mersilene mesh is an alternative substance combining the advantages of permanent implant cover with low rates of infection and ready availability. We describe our experiences in the use of Mersilene mesh covered intraorbital implants in 14 patients. Our findings suggest that Mersilene mesh could be considered as a possible alternative choice of material for covering intraorbital implants.

Adolescent↗
PubMed1992

Single and combined effects of the vitamin D analogue KH1060 and cyclosporin A on mercuric-chloride-induced autoimmune disease in the BN rat.

Mercuric chloride induces in BN rats a self-limiting systemic autoimmune disease characterized by proliferation of autoreactive CD4+ T lymphocytes, polyclonal activation of B lymphocytes, and the development of an anti-glomerular basement membrane (GBM) nephritis with concomitant nephrotic range proteinuria. We have used this model of autoimmune disease to test the immunosuppressive ability of a novel vitamin D3 analogue KH1060. This compound prevents autoimmune manifestations including proteinuria, serum IgE, and serum anti-laminin antibodies in a dose-dependent manner, as does cyclosporin A (CyA). When dosages of KH1060 capable of partial reduction of proteinuria without causing significant hypercalcaemia are combined with small dosages of CyA also capable of partial prevention of proteinuria, an additive effect is seen, leading to complete prevention of proteinuria and substantial reductions in serum IgE and anti-laminin levels. Possible mechanisms of action are discussed and it is suggested that KH1060 could prove useful as an immunosuppressive agent in the treatment of autoimmune diseases.

Animals↗
PubMed1992

The histology at various stages of acute rejection in concordant xenogeneic heart transplantation. A sequential study in rodents.

In an attempt to describe early morphologic changes in heterotopic xenogeneic heart transplantation a sequential study was performed in a hamster-to-rat model. Mild morphologic changes observed after four to six h were characterized by slight interstitial edema and focal myocyte damage with fragmentation and loss of myofibrillar elements. No lymphocytic infiltration appeared. Moderate morphologic changes observed after 12-24 h were characterized by moderate interstitial edema, and the appearance of mild hemorrhage and scattered extravasated neutrophilic granulocytes. The myocardium had more widespread areas with myocyte damage, sometimes with small foci of necrotic cells and adjacent neutrophilic granulocytes and macrophages. Vascular changes with perivascular edema and swelling of the endothelium were seen and a few neutrophilic granulocytes could be found in the vessel walls. No lymphocytic infiltration appeared. Severe morphologic changes observed after 44-48 h or at the time of complete rejection were characterized by severe interstitial hemorrhage, appearance of widespread necrosis and marked vascular changes with development of leukocytoclastic-like vasculitis, possibly with thrombosis. Only a few lymphocytes appeared. The findings were essentially different from those observed in allogeneic heart transplantations, where classical first-set allograft rejection was seen. In normal donor hearts and syngeneic transplanted hearts used as controls, no significant morphologic changes were demonstrated. On the basis of this study we consider xenogeneic acute rejection to be primarily of the humoral type.

Animals↗
PubMed1992

Survival, function, morphology and serological aspects of rat renal allografts. Effect of short-term treatment with cyclosporine A, anti-CD4 and anti-interleukin-2 receptor monoclonal antibodies.

The aim of this study was to investigate the effect of short-term treatment with cyclosporine A (CyA) combined with anti-CD4 (OX-38) and anti-interleukin-2 receptor (OX-39) monoclonal antibodies (MAbs) on graft survival, graft function, morphology, and anti-donor antibody levels in a BN-to-LEW rat kidney transplantation model. Spontaneous rejection occurred at 9.3 days (range 9-10 d). Administration of CyA (12.5 mg/kg/d) for 14 days prolonged graft survival to 33 days (range 23-40 d, P less than 0.02). Supplementing with OX-38 and OX-39 100 micrograms/kg/d, given i.p. from days 0 to 7, further prolonged graft survival to 70 days (range 38- greater than 100 d, P less than 0.02 vs controls and CyA group). One of seven recipients had good graft function for more than 100 days. A three-fold increase of the MAb dosage did not improve mean graft survival (53.5 d), but three of eight recipients had well functioning grafts for greater than 100 days. Kidney function was characterized by reduced creatinine clearance, also in the recipients with long-term graft survival, and a defect in concentrating urine creatinine with subsequent pronounced increase in urinary output. Graft histology showed a complex pattern of interstitial alterations including mononuclear cell infiltration, fibrosis, tubular atrophy and vascular damage with intimal/endothelial cell hyperplasia and perivascular inflammation. In nine of 10 MAb-treated recipients with graft survival greater than 60 days, granular deposits of immunoglobulins and C3 were found by immunofluorescence microscopy (IFM). The deposits were localized in the glomerular capillaries and mesangium. IFM in MAb-treated control animals could not demonstrate any deposits. Flow cytometric evaluation of posttransplant serum samples against donor target cells showed increasing amounts of anti-donor antibodies until the time of rejection, while recipients with long-term graft function had moderately positive cross-matches up to two months after transplantation. Hereafter antibody titres decreased and cross-matches at the time of sacrifice were again negative. The morphological findings and the flow cytometric cross-match results seem to indicate a postponed antibody-mediated type of rejection. The reason why some kidney recipients showed decreasing antibody titres and stable long-term graft function is unclear.

Animals↗
PubMed1992

Antagonist capacity of felodipine on cyclosporin A nephrotoxicity in the rat.

Functional and morphological cyclosporin A (CsA) nephropathy has been attributed to a CsA-induced constriction of the afferent glomerular arteriole. Calcium-channel blockade with nifedipine prevented the development of short-term functional nephrotoxicity in CsA-treated rats. This study investigated whether the calcium antagonist felodopine, a structural analogue of nifedipine, which reduces renal tubular fractional sodium reabsorption, could prevent both short- and long-term functional and long-term morphological CsA nephropathy. In short-term experiments, four groups of Spraque-Dawley rats (n = 39) were given CsA (either 0 or 12.5 mg/kg per day by daily gastric intubation for 2 weeks), and felodipine (0 or 30 mg/kg per day) in the diet. In long-term experiments, rats (n = 39) were given CsA (12.5 mg/kg per day for 16 weeks), and felodipine (0 or 30 mg/kg per day in the diet). Renal function was investigated with clearance methods (inulin, lithium, and sodium), and kidney morphology was studied by light-microscopy. In short-term experiments, CsA treatment reduced GFR (730 versus 1181 microliters/min per g kidney weight (KW), P < 0.05) and CLi (130 versus 271 microliters/min per gKW, P < 0.02). Felodipine decreased proximal fractional reabsorption (PFR) (67.5% versus 71.4%, P < 0.05) and increased CNa (15.9 versus 8.4 microliters/min per gKW, P < 0.02) as compared to controls. In CsA-treated rats felodipine increased C in (1260 versus 730 microliters/min per gKW, P < 0.05) and CLi (319 versus 130 microliters/min per gKW, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Monoclonal antibody treatment (anti-CD4 and anti-interleukin-2 receptor) combined with cyclosporin A has a positive but not simple dose-dependent effect on rat renal allograft survival.

The use of monoclonal antibodies (MoAbs) in experimental and clinical organ transplantation is of increasing interest since this treatment seems to offer an opportunity for specific immunomodulation. In a rat kidney allograft model, Cyclosporin A (CyA) treatment (12.5 mg/kg/d, day 0-14) was combined with murine anti-rat CD4 (MRC OX-38) and murine anti-rat IL-2R (MRC OX-39) MoAbs at doses of 100 or 300 micrograms/kg/d (day 0-7) and plasma concentrations of the murine MoAb were determined. In both groups receiving combined treatment with CyA and MoAb, graft survival was prolonged to an average of 65 days, compared to a graft survival of 9-10 days in non-treated recipients. Further, the data showed a beneficial effect of CyA + MoAb treatment versus CyA alone (graft survival 32 days). The threefold increased MoAb dose did not seem to improve graft survival or function. Treatment with OX-38 + OX-39 at a dose of 100 micrograms/kg/d each resulted in plasma levels of 280 ng/ml 14 days after transplantation. Corresponding values after the administration of 300 micrograms/kg/d were 1800 ng/ml in graft recipients as well as controls. These findings indicate that the effect of MoAbs in complex organ transplantation models is not simply dose dependent and that in vitro assays are of limited value in predicting the effect of a given MoAb when used in vivo. The determination of MoAb plasma levels, however, may be a useful tool in defining optimal MoAb administration and to monitor therapeutically effective plasma levels.

Animals↗
PubMed1991

Flush perfusion of rabbit kidneys with autogeneic, allogeneic and xenogeneic blood.

A simple perfusion model was developed to study the events that lead to rejection of renal xenografts. Flush perfusion of the kidneys of 24 rabbits was carried out with blood from rabbits, cats, or humans. Light microscopy showed alterations with neutrophilic granulocytes margination of the vessels after only 15 min of perfusion. In the experiments with human blood the immunofluorescence microscopy showed deposits of immunoglobulins and complement factor III. This simple method is therefore a useful way of studying perfusion in renal xenografts.

Animals↗
PubMed1990

Treatment with total lymphoid irradiation, cyclosporin A and a monoclonal anti-T-cell antibody in a hamster-to-rat heart transplantation model: graft survival and morphological analysis.

Treatment with preoperative total lymphoid irradiation and post-transplant cyclosporin A has been shown to have a synergistic effect on graft survival in allo- and xenotransplantation. Specific monoclonal antibodies against T cells and T cell subpopulations could offer new ways of preventing graft rejection in xenotransplantation. Graft survival and histology were examined after total lymphoid irradiation plus cyclosporin A treatment versus cyclosporin A plus a monoclonal antibody in a concordant, heterotopic, hamster-to-rat heart transplantation model. Preoperative total lymphoid irradiation was given at a dose of 1.25 Gy, 12 times over a period of 3 weeks. Cyclosporin A at a dose of 12.5 mg/kg per day was administered perorally and OX-19, a pan T cell monoclonal antibody, was given as intraperitoneal injections at doses of 100 micrograms or 500 micrograms/kg per day from day 0 until graft rejection. While total lymphoid irradiation alone prolonged graft survival to 9.4 days, total lymphoid irradiation plus cyclosporin A extended graft survival to a mean of 22 days. Cyclosporin alone or combined with the monoclonal antibody could not increase graft survival significantly when compared to untreated animals, which rejected their grafts within 3.7 days. Vascular rejection was the characteristic morphological finding, even after some weeks of excellent graft function. In conclusion, total lymphoid irradiation and cyclosporin A had a synergistic effect on graft survival in this concordant xenotransplantation model, although recent impressive results from other groups could not be reproduced. Total lymphoid irradiation combined with cyclosporin A appears to delay a primary humoral graft rejection, while the mechanism of rejection, judged by histology, stays the same.

Analysis of Variance↗
PubMed1990

Nephrotoxicity of cyclosporin A in patients with newly diagnosed type 1 diabetes mellitus.

Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12 to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance (17 +/- 3 vs 28 +/- 5 ml min-1 1.73-m-2, p less than 0.05). The fractional proximal reabsorption was increased (0.82 +/- 0.03 vs 0.78 +/- 0.03, p less than 0.05), and the fractional distal sodium reabsorption reduced (0.88 +/- 0.03 vs 0.94 +/- 0.02, p less than 0.05). These results are in accordance with the hypothesis that the nephrotoxic effect of cyclosporin A results from a preferential constriction of afferent glomerular vessels. One year after withdrawal of the drug, all variables were similar in the two groups, except for blood glucose control which was worse in the cyclosporin A treated group. When corrected for differences in blood glucose control it appeared that in three out of nine patients glomerular filtration rate had not completely returned to the reference range of the placebo group. We conclude that the nephrotoxic side-effects of cyclosporin A treatment for 1 year are reversible. There are, however, signs of minor and perhaps chronic renal injury.

Adult↗
PubMed1990

Hope for successful xenografting by immunosuppression with monoclonal antibody against CD4, total lymphoid irradiation and cyclosporine. Six months' survival of hamster heart transplanted into rat.

Hamster hearts were transplanted to rats, and the effects of combinations of total lymphoid irradiation (TLI), cyclophosphamide, cyclosporine A (CyA) and monoclonal antibodies (MAB) were investigated. Controls not immunosuppressed rejected their xenograft in 3 to 5 days, while combination immunosuppression including MABs against CD4 or IL-2-receptors extended graft survival significantly. In one case, the graft was still functioning 180 days after transplantation, which is the longest survival seen in this model. The use of specific MABs may open a new era for both xeno- and allo-transplantation.

Animals↗