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Biomedical subjects

E Heineman

Publications and source records attributed to E Heineman.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effects of donor pretreatment with antilymphocyte serum and cyclosporin on rejection and graft-versus-host disease after small bowel transplantation in immunosuppressed and nonimmunosuppressed rats.

After fully allogeneic small bowel transplantation, both graft-versus-host disease (GVHD) and rejection may occur. Donor pretreatment may prevent GVHD, but this sometimes leads to accelerated graft rejection. To study a possible balance between GVHD and rejection, fully allogeneic total orthotopic small bowel transplantation was performed in rats using the WAG-to-BN donor-host combination. Untreated control grafts were rejected in 16.6 +/- 2.7 days (mean +/- SEM), and 35% of the animals had mild, transient GVHD. Pretreatment of the donor with antilymphocyte serum on days -2 and -1 before grafting, with antilymphocyte serum on days -2 and -1 before grafting, with antilymphocyte serum on days -2 and -1 before grafting, either intravenously or intraperitoneally, completely eliminated the occurrence of clinical GVHD but led to significantly shortened survival times (12.3 +/- 0.8 and 10.3 +/- 0.9 days, respectively). Donor pretreatment with 50 mg/kg cyclosporin (CyA) on days -2 and -1 prolonged graft survival significantly to 22.1 days but had no significant effect on the incidence of GVHD. Administration of 25 mg/kg CyA on days 0, 1, 2, 4, and 6 after grafting prolonged survival to 38.3 days with no evidence of GVHD. Pretreatment of the donor with antilymphocyte serum (ALS), combined with the same postoperative, short-term CyA regimen, increased survival to more than 50 days, again with no evidence of GVHD. When CyA was used as both donor pretreatment and postoperative therapy, there was no survival advantage compared to the use of postoperative CyA alone. These results show that an in vivo balance between GVHD and rejection exists and that abrogation of GVHD leads to accelerated rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Long-term survival of DLA-matched segmental small-bowel allografts in dogs.

The aim of this study was to investigate the combined effect of DLA matching and immunosuppressive therapy on the survival of segmental small-bowel allografts in dogs. Orthotopic segmental small-bowel transplantations (25 to 30% of total small bowel length) were performed in two stages: first a heterotopic segmental small bowel transplantation, followed after 5 to 8 weeks by a second-stage operation during which the heterotopic graft was placed in an orthotopic position and the native small bowel was resected. All dogs received cyclosporine immunosuppression. Control dogs (n = 4), subjected to total enterectomy, survived 37.3 +/- 7.1 days (mean +/- SEM). Recipients of DLA-mismatched small bowel grafts (n = 6) survived 113.2 +/- 37.0 days, which was a significantly shorter time than dogs with a DLA-matched graft (n = 6, 211.5 +/- 38.8 days, P < 0.05). None of the matched allografts was rejected during CsA treatment, whereas four of six mismatched grafts were (P < 0.05). The control dogs uniformly showed progressive weight loss, steatorrhea, and hypoalbuminemia. The dogs with DLA-mismatched grafts did not regain initial body weight, whereas animals with DLA-matched grafts recovered preoperative weight after 20 weeks. Both transplanted groups showed near-normal fecal fat excretions and constant serum albumin, cholesterol, and triglyceride levels, whereas serum total protein levels increased during follow-up. We conclude that segmental small bowel transplantation between DLA-matched donor-recipient pairs results in long-term survivors with an adequate nutritional status. This may have important implications for future living-related small-bowel transplantation.

Animals↗
PubMed1993

The value of in vivo electrophysiological measurements for monitoring functional adaptation after massive small bowel resection in the rat.

The process of functional adaptation after extensive small bowel resection is complex and imprecisely understood. In vivo electrophysiological measurements for monitoring the functional adaptive process after massive small bowel resection in Brown-Norway rats were evaluated. Rats underwent either a sham operation (SH) or a 90% small bowel resection (SB). Standard rat chow was fed in unlimited quantities. At three or 10 weeks after operation, jejunal and ileal transepithelial potential differences (PD, mV) were determined. Electrogenic ion transport in the villus was measured after glucose (sodium coupled active glucose absorption; PD-glu) and in the crypt, after theophylline infusion (theophylline stimulated chloride secretion; PD-theo). Biopsies were taken simultaneously. Each experimental group consisted of three to five animals. At three weeks the PD-theo and PD-glu in SB rats were significantly lower than in SH rats in both jejunal and ileal segments. At 10 weeks PD-theo and PD-glu were significantly diminished in the jejunal segment of the SB rats compared with the SH rats. The values of PD-theo and PD-glu in the ileal segments were, however, no longer different between the two groups. Three and 10 weeks after operation the length of the villi in the SB group was increased significantly compared with the SH controls. These results indicate that in the early phase of adaptation in vivo electrophysiological variables do not correlate with histological changes in the SB rats. This might be due to cell immaturity resulting from an increased rate of cell turnover or lack of intercellular tight junctions. This hypothesis is supported by a recovery of PD responses in the ileum 10 weeks after resection.

Adaptation, Physiological↗
PubMed1992

Functional aspects of small-bowel transplantation in rats.

Although clinical small-bowel transplantation is still severely hindered by rejection of the graft, prolonged graft survival can be achieved by using cyclosporin A in several experimental models of small-bowel transplantation. In an immunologically quiescent phase after transplantation, the important question arises whether a small-bowel allograft has enough functional capacity to maintain a normal nutritional status. We investigated the functional capacity of orthotopic small-bowel transplants and evaluated the ability of the total small-bowel transplant to absorb orally given cyclosporin in the early postoperative period and the effect of this oral cyclosporin treatment on allograft survival as compared with intramuscular administration. Between 3 and 7 months postoperatively, recipients of syngeneic and allogeneic total small-bowel transplants and syngeneic jejunal segmental grafts had significantly decreased serum triglyceride levels. Total serum protein and albumin concentrations, serum cholesterol values, fecal fat excretion, and percentage of split fatty acids were normal. One year after transplantation the weight in the groups transplanted with a total small-bowel graft was not different from age-matched untreated controls. Animals grafted with a segmental graft, however, showed a significantly impaired growth and had not reached a normal weight 1 year after transplantation. Growth was also significantly impaired after near-total small-bowel resection. These animals had to be killed because of their poor condition. Cyclosporin absorption after small-bowel transplantation equalled that in normal controls. Graft survival after intramuscular treatment, however, was significantly better than after oral treatment.

Absorption↗
PubMed1991

Electrophysiologic and histological monitoring of MHC-matched and mismatched canine intestinal allografts.

Intestinal transplantation (ITx) has potential applications for the treatment of short-bowel syndrome (SBS). A major obstacle to its clinical use is rejection, which may partly be overcome by major histocompatibility complex (MHC) matching. At present, it is impossible to predict accurately the early onset of rejection. The aim of this study was to assess the value of in vivo measurements of transepithelial potential difference (PD) for the determination of rejection in MHC-matched and -mismatched canine ITx. A heterotopic ITx was performed in MHC tissue-typed Beagle dogs. Two ileostomies were created for PD monitoring and histology. Via one ileostomy, a well-defined segment of the IT, was isolated by a double balloon catheter and the intraluminal PD was measured in reference to a subcutaneous electrode. The PD responses during perfusion of a theophylline solution (crypt cell stimulation, PD theophylline) and during perfusion of a glucose solution (villus cell stimulation, PD glucose) were assessed. The results of in vivo PD measurements were compared with simultaneously obtained histology specimens. Four groups of dogs were studied: group 1 (controls, n = 10) ileal autotransplants; group 2 (n = 6) ileal allotransplants, fully mismatched; group 3 (n = 3) ileal allotransplants, 1 haplotype identical; and group 4 (n = 5), ileal allotransplants, fully matched. No immunosuppression was given. All dogs of group 1 survived indefinitely and both PD and histology showed no abnormalities. In group 2, 3, and 4 the onset of histological changes related to rejection corresponded well with decreased PD responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Detection of canine intestinal allograft rejection by in vivo electrophysiologic monitoring.

The aim of this study was to evaluate the significance of in vivo measurements of electrophysiologic parameters for the detection of canine small bowel (SB) allograft rejection. In dogs of group I (n = 17) a heterotopic SB autotransplantation was performed. Dogs of group II (n = 8) received a heterotopic SB allograft in a fully mismatched donor-recipient combination. No immunosuppression was given. All grafts were monitored regularly by in vivo measurements of transepithelial potential differences (PDs) and by biopsies of the grafts. The overall technical failure rate was 36% caused by thrombosis at the vascular anastomosis in most cases. All successful autografts survived the experimental period and showed physiologic PD responses after stimulation by both a theophylline solution and a glucose solution. The successful allografts survived 5.5 +/- 0.2 days (mean +/- SEM); the transepithelial PDs showed normal responses at postoperative day 3, but showed decreased responses at day 5 (P less than 0.05) and reversed responses at day 6 (P less than 0.05). The diminished PD responses correlated well with the onset of histologic alterations characteristic of rejection. This study demonstrates that serial monitoring of transepithelial PD responses is a noninvasive method to detect acute SB allograft rejection.

Animals↗
PubMed1991

Value of in vivo electrophysiological measurements to evaluate canine small bowel autotransplants.

This study aimed to develop a non-invasive method for in vivo measurement of the transepithelial potential difference in the canine small bowel and to evaluate this parameter in small bowel autotransplants. In group 0 (control group, n = 4), two intestinal loops were created without disturbing their vascular, neural, and lymphatic supplies. In group I (successful autotransplants, n = 11), two heterotopic small bowel loops were constructed. Long term functional sequelae of vascular, neural, and lymphatic division were studied. Group II (n = 6) consisted of dogs with unsuccessful autotransplants suffering thrombosis of the vascular anastomosis, which resulted in ischaemic small bowel autografts. In group I, values of spontaneous transepithelial potential difference, an index of base line active electrolyte transport, were significantly lower compared with group 0 (p less than 0.05), probably as a result of denervation of the autotransplants. Both theophylline and glucose stimulated potential difference responses, measuring cyclic adenosine monophosphate mediated chloride secretion and sodium coupled glucose absorption respectively, showed negative luminal values in group I at all time points after transplantation. These transepithelial potential difference responses diminished progressively with time. From day 21 onwards both theophylline and glucose stimulated potential difference responses were significantly less than the corresponding responses at day seven (p less than 0.05). Morphometric analysis showed that the reduction of transepithelial potential difference responses preceded degenerative mucosal changes in the heterotopic small bowel autografts. In group II, potential difference responses to theophylline and glucose showed positive luminal values (p<0.01 v group I), probably as a result of passive potassium effusion from necrotic enterocytes.

Animals↗
PubMed1991

Total orthotopic allogeneic small bowel transplantation in rats: effect of allograft irradiation combined with cyclosporine-A therapy.

Rejection and graft versus host disease are prominent features in small bowel allotransplantation in rats. Cyclosporine treatment of the recipient and irradiation of the donor were used to circumvent these phenomena in the WAG to brown Norway rat model. Irradiation of the donor with five or 10 Gy did prevent graft versus host disease but resulted in a more vigorous rejection of small bowel allografts in untreated recipients (mean (SEM) survival times of 11.5 (0.4) (n = 8) and 7.5 (0.9) (n = 11) days respectively, versus 16.6 (2.6) days (n = 17), p less than 0.01). Cyclosporine treatment of the recipient (25 mg/kg on days 0, 1, 2, 4, and 6 after transplantation) led to a mean (SEM) survival time of 38.3 (8.5) days (n = 10); 20% of the animals developed graft versus host disease. Combined with 5 Gy donor pretreatment, a similar survival was obtained without occurrence of graft versus host disease. However, cyclosporine treatment combined with 10 Gy led to a significant shortening of graft survival (23.1 (6.8) days, n = 9). These results suggest that although irradiation is very effective in preventing graft versus host disease, high dosages may accelerate rejection either by making the graft more vulnerable to rejection or by completely removing the immuno-suppressive effect of graft versus host disease.

Animals↗
PubMed1990

The limited efficacy of cyclosporine in preventing rejection and graft-versus-host disease in orthotopic small bowel transplantation in rats.

The effect of different schedules of cyclosporine treatment on the survival of small bowel allografts was studied in rats. The administration of a short course of CsA (15 mg/kg on days 0, 1, 2, 4, and 6) had no beneficial effect on graft-vs.-host disease and survival time of the recipient compared with untreated controls. CsA, 25 mg/kg for 1 or 2 weeks prolonged survival significantly (38.3 +/- 3.8 and 42.5 +/- 2.7 vs. 16.6 +/- 2.7, P less than 0.01). When combined with maintenance therapy, 15 mg/kg of CsA 3 times weekly until day 100, only 7 of 30 rats survived more than 100 days. In addition, GVHD was not consistently abrogated in these groups. Only high doses of CsA (25 mg/kg on days 0-6, 15 mg/kg on days 7-13, followed by maintenance therapy) could prevent the onset of GVHD, although the survival time of the transplants was not prolonged compared with untreated controls due to a toxic side effect of CsA on the transplants. It can be concluded that CsA used as monotherapy is ineffective in consistently ameliorating GVHD and rejection in the WAG-BN rat model. This model exhibits at least some of the immunological problems seen in large animal models and can be useful in studying combinations of immunosuppressive drugs or methods that may be applicable to small bowel transplantation in man.

Animals↗