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E Kemp

Publications and source records attributed to E Kemp.

At least 19 recordsLinked to original sources
PubMed1995

Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.

Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.

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PubMed1994

Immunosuppressive effect of total body irradiation and cyclosporine A on graft survival and the lymphatic system in a cardiac hamster-to-rat transplantation model.

The aim of the study was to evaluate the effect of total body irradiation (TBI) and cyclosporine A (CyA) on graft survival and the lymphatic system in a concordant hamster-to-rat heart transplantation model, and to compare these effects with those of total lymphoid irradiation (TLI). Preoperatively TBI was given as a single dose of 5 Gy, CyA was given intramuscularly at a dose of 10 mg/kg/day. TBI prolonged graft survival to seven days. Combined TBI and CyA prolonged graft survival to ten days. The effect of TBI on graft survival, total white blood cell count (WBC) and differential counts was reproducible but not as distinct as the effect of TLI. Analysis of changes in WBC and differential counts combined with the morphology of the grafts at rejection and of spleens from TBI- and CyA-treated animals indicates a reproducible immunosuppressive effect of TBI and a severe type of acute humoral rejection with vasculitis and cellular infiltrates dominated by macrophages and neutrophilic granulocytes. In conclusion, we find TBI a simple pretreatment which may be useful in combination with other immunosuppressive treatment as preoperative induction and depletion therapy.

Animals↗
PubMed1994

Anti-CD4 monoclonal antibody treatment in combination with total lymphoid irradiation and cyclosporin A in hamster-to-rat cardiac transplantation. Morphological features of heart grafts, recipient spleens and lymph nodes.

Significantly prolonged graft survival (GS) of hamster hearts transplanted heterotopically into rats can be achieved by different immunosuppressive treatment strategies. The exact mechanism of graft rejection is unclear, but it seems to be a primarily humoral, antibody-mediated type of rejection. The histopathology of long-term surviving grafts is controversial and the morphology of lymphoid tissue in spleens and lymph nodes as the possible site of anti-donor antibody formation has not previously been investigated. This report demonstrates a significantly prolonged GS in hamster-to-rat cardiac transplantation after combined treatment with total lymphoid irradiation (TLI), cyclosporin A (CyA) and anti-CD4 monoclonal antibodies (MAb), where long-term GS (> 100 days) could be achieved in a few animals. The histopathology of heart grafts showed predominantly chronic vascular changes with endothelial proliferation, intimal thickening and vessel obliteration. No substantial cellular reactivity in terms of mononuclear/lymphoid cell infiltration could be demonstrated in rejected grafts. Spleens and lymph nodes were characterized by a profound global reduction in lymphoid tissue after preoperative TLI. Although subsequent lymphoid regeneration was depressed due to postoperative immunosuppression, a significant increase in IgM-positive plasma cells was observed, supporting evidence of an antibody-mediated mechanism of graft rejection. The role of CD4+ cells is unclear, but anti-donor antibody formation might involve T-cell help.

Animals↗
PubMed1994

[Xenograft].

The ultimate purpose of research in xenografting (cross-species transplantation) is successful transplantation of tissue and organs from animals to human patients. Success in the clinical application of xenografting would mean an end to the shortage of donor organs. Xenografts are classified as concordant or discordant, depending on rejection factors and histology. Several clinical attempts have been made since 1963, but success has been limited. However, great progress has been made in laboratory attempts; and the procedures should now be given clinical trials. This success has been due to the efficacy of many of the newly developed immunosuppressive drugs. Discordant xenografting is still problematic, and in this type of transplantation the most promising approach would seem to be with isolated cells or cell clusters.

Animals↗
PubMed1994

Long-term cyclosporin A nephrotoxicity in the rat. Evaluation of a morphological scoring system and of co-treatment with isradipine.

Cyclosporin A (CyA) nephrotoxicity was examined in Spraque-Dawley rats given CyA (12.5 (n = 45) or 25 (n = 45) mg/kg/day perorally for 16 weeks. Control rats (n = 45) received CyA vehicle. All rats were given either isradipine (ISRA) 1 or 5 mg/kg/day orally, or isradipine vehicle. Fifteen rats died from interstitial pneumonia caused by Staphylococcus xylosus. A predefined morphological CyA nephrotoxicity scoring system, based on semiquantitative scores for basophilic tubules and for interstitial fibrosis, performed on hematoxylin-eosin-stained tissue, yielded mean scores for basophilic tubules of 0.2 (range 0-1) in controls, 1.4 (range 0-3) in rats given CyA 12.5 mg/kg/day (p < 0.001), and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001 as compared to controls). Rats given CyA were grouped according to their score for interstitial fibrosis: 0.2 (range 0-1) in CyA 12.5 mg/kg/day and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001). When scores for basophilic tubules and interstitial fibrosis were pooled, none of the control rats had a score above 1, while 47% of the low-dose and 95% of the high-dose rats scored above 1. Thus, this CyA nephrotoxicity scoring system provided an easy, efficacious, and reproducible identification of rats with morphological CyA nephrotoxicity, and may be of clinical interest in the assessment of CyA nephrotoxicity. Kidney tissue from rats not treated with isradipine was further investigated with periodic acid-Schiff (PAS) with and without diastase treatment, and with Sirius Red. The latter confirmed the increase in connective tissue following tubular atrophy in CyA-treated rats. PAS reaction disclosed diastase-resistant positivity in the glomerular arterioles (score in controls: mean 0.4, range 0-1, in CyA 12.5 mg/kg/day mean 2.2, range 1-3, p < 0.001 as compared to controls; in CyA 25 mg/kg/day mean 1.1, range 0-2, p < 0.005 as compared to controls, p < 0.05 as compared to CyA 12.5 mg/kg/day). Furthermore, the straight part of the distal tubules of rats given the highest CyA dose contained considerable amounts of glycogen. The significance of this finding is unknown. Renal functional studies confirmed previous results since CyA decreased inulin clearance (Cin) from 1.2 +/- 0.5 to 0.8 +/- 0.3 ml/min/g kidney weight (kW) (p < 0.05), and lithium clearance (CLi) was reduced from 263 +/- 113 to 119 +/- 61 microliters/min/gKW (p < 0.001). Isradipine had no significant effect.

Animals↗
PubMed1994

An ultrastructural analysis of concordant and discordant cardiac xenografts in unmodified recipients. A sequential study in rodents with special reference to endothelial cell changes in the microvascular system.

Ultrastructural changes in endothelial cells in a hamster-to-rat and guinea pig-to-rat heart transplantation model are described. In the hamster-to-rat model, changes were minimal with an increase in cytoplasmic vesicles 4-6 h after transplantation. 16-24 h after transplantation larger vesicles appeared and the basement and cell membranes were less well defined. 42-48 h after transplantation the changes had progressed with destruction of cell membranes and the appearance of extravasated changes had progressed with destruction of cell membranes and the appearance of extravasated erythrocytes. At the time of complete rejection, changes had further progressed with widespread endothelial cell destruction and infiltration of neutrophilic granulocytes and macrophages, and large amounts of fibrin were present. In the guinea pig-to-rat model, changes were characterized by the appearance of platelets in close contact with the endothelium of the capillaries 1-3 min after transplantation. 4-6 min after transplantation the basement membranes as well as the cell membranes were affected with indistinct borders and interruption. Occasionally fusion of platelets and endothelial cell membranes was demonstrated. In the grafts examined 7-9 min after transplantation, changes had further progressed. Massive aggregation of platelets now appeared in relation to remnants of endothelial cells. Signs of microvascular damage appeared in both models, but with different morphology. In hamster grafts, endothelial cell activation is indicated by gradual changes in the cell membranes resulting in vascular damage and infiltration of the grafts by macrophages and neutrophilic granulocytes. In the guinea pig grafts, activation of endothelial cells results in platelet aggregation, formation of microthrombi, and subsequent tissue damage. Even though antibody and complement are involved in both types of rejection the basic mechanisms are different.

Animals↗
PubMed1993

Anti-CD4 monoclonal antibody treatment combined with total lymphoid irradiation and cyclosporin A in hamster-to-rat cardiac transplantation. Analysis of lymphocyte subsets and anti-donor xenoantibodies.

Combined treatment with total lymphoid irradiation and cyclosporin A results in prolonged graft survival in concordant xenogeneic cardiac transplantation, but reproducible long-term graft acceptance has proved to be difficult. Anti-CD4 monoclonal antibody treatment has been successful in inhibiting heart graft rejection in allogeneic models. Used as monotherapy in a concordant xenogeneic model for pancreatic islet transplantation, prolonged graft survival has been reported; however, no beneficial effect on primarily vascularized heart grafts was noted. The object of this investigation was to combine these treatment strategies with respect to reproducible long-term hamster heart graft survival in rats, to monitor the effect on lymphocyte subpopulations, and to determine possible anti-donor antibody formation correlated to time of rejection. Graft survival after combined preoperative total lymphoid irradiation and postoperative cyclosporin A + anti-CD4 monoclonal antibody treatment was prolonged from 14 to > 100 days (compared to spontaneous graft survival of three to four days), with long-term graft function in four of 19 recipients. Total white blood counts in the postoperative course were characterized by an unproportional increase of Ig+ cells and an incomplete recovery of CD4+ cells. Flow-cytometric analysis of anti-donor antibodies showed low levels of preformed antibodies and increasing amounts of strain-, but not donor-specific antibodies, correlated to the time of rejection. Long-term survivors with functioning grafts at the time of sacrifice had an initially moderate antibody increase with subsequent decrease to baseline levels. Our results indicate that total lymphoid irradiation combined with cyclosporin A and anti-CD4 monoclonal antibodies can prolong graft survival significantly in concordant hamster-to-rat cardiac xenotransplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Evidence for a primarily humoral rejection mechanism in concordant xenogeneic heart transplantation. A sequential immunohistological study in a hamster-to-rat model.

Heterotopic heart transplantations in an unmodified hamster-to-rat model were studied sequentially by immunohistochemical analysis. Monoclonal mouse anti-rat antibodies against B cells, T cells, macrophages and neutrophilic granulocytes (MRC OX-19, MRC OX-38, MRC OX-8, MRC OX-22, MRC OX-33, MRC OX-41 and MRC OX-42) were used in an indirect immunoperoxidase technique and monoclonal mouse anti-rat IgM and IgG were used for immunofluorescence. In grafts investigated after 6 h (N = 8) minimal infiltration of macrophages was demonstrated with MRC OX-41+ and MRC OX-42+ cells. No T- or B cells were seen. In a few cases, deposition of IgG and IgM was seen related to the endothelium of larger vessels. In grafts examined 24 h after transplantation (N = 10) the number of MRC OX-41+ and MRC OX-42+ cells had increased and in half of the cases IgM and IgG were located in relation to endothelial cells of larger vessels. In grafts investigated 48 h after transplantation (N = 8) the infiltration with MRC OX-41+ and MRC OX-42+ cells had further increased and a few scattered MRC OX-19+ and MRC OX-8+ cells appeared. At this time all but one heart had deposition of IgG and IgM in the vessel walls. Upon complete rejection (N = 8) diffuse infiltration of MRC OX-41+ and MRC OX-42+ cells was seen, but still only a few scattered T cells could be demonstrated. At this time IgG an IgM deposition appeared in all vessels and was also located in relation to the capillaries. These results further support our hypothesis that acute xenograft rejection in this animal model is primarily of the humoral type.

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