Genetic aspects of graft-vs-host reaction after small bowel transplantation with and without mesenteric lymphadenectomy.
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Biomedical subjects
Publications and source records attributed to J Klempnauer.
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In inbred streptozocin-induced diabetic rats, the long-term function of different endocrine pancreatic isografts was compared. Isolated islets transplanted into the portal vein showed a progressive deterioration of function over time. In contrast, islets under the kidney capsule sustained a constant long-term function controlling all clinical signs of diabetes. Recipients of kidney subcapsular islets displayed normal growth rate, peripheral serum glucose and insulin levels, and metabolic parameters. However, their functional reserve was markedly reduced as revealed by diminished glucose tolerance and reduced insulin-secreting capacity after an intravenous glucose challenge. Vascularized whole-organ pancreatic grafts with portal venous drainage led to complete normalization of all parameters determined in this study. This study showed that the long-term function of islets transplanted under the kidney capsule is superior compared with islets transplanted into the portal vein.
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The adequate management of the exocrine secretion of vascularized pancreas transplants is still controversial. Basically, the exocrine graft secretion may either be suppressed by obstruction of the pancreatic ducts or preserved by drainage into the recipient's enteric or urinary tract. In a model of isogenic pancreas transplantation in streptozotocin diabetic rats the impact of preserved versus suppressed exocrine secretion on the quality of endocrine graft function was investigated. Preservation of the exocrine secretion was accomplished by pancreaticoduodenal transplantation, while duct ligation was used to suppress the exocrine secretion. Endocrine graft function was monitored by determination of non-fasting blood glucose levels, intravenous glucose tolerance tests, peripheral insulin levels, water and food intake as well as urine and faeces production. Suppression of the exocrine graft secretion induced acinar atrophy, proliferation of pancreatic ducts, interstitial cell infiltration and fragmentation of islets of Langerhans, while drainage of the exocrine graft secretion completely preserved the architecture of the transplant. Despite the fundamental structural changes induces by exocrine suppression no deterioration of endocrine graft function was noted within the observation period of one year. Both techniques were equally effective in ameliorating the diabetic hyperglycemia, hypoinsulinemia, reduced glucose tolerance, polydipsia, polyphagia, polyuria and restored normal growth rate and general health of diabetic pancreas graft recipients. Thus it can be concluded that suppression of the exocrine secretion does not impair the quality of endocrine function of pancreas transplants.
Graft morphology and endocrine function following vascularized pancreas transplantation by different surgical techniques were determined in streptozotocin-diabetic rats. Eight different surgical techniques were studied. Intestinal drainage of exocrine secretion was accomplished by pancreaticoduodenal transplantation or by utilizing only a patch of the donor duodenum for duodenojejunostomy. Following pancreaticoureterostomy and pancreaticocystostomy, the graft's exocrine secretion was drained to the recipient's urinary tract. The exocrine secretion was allowed to drain freely into the recipient's peritoneal cavity following transverse or longitudinal incision of the common bile duct. Exocrine secretion was suppressed either by duct ligation or by retrograde ductal injection of prolamine. Following enteric or urinary exocrine graft drainage, the architecture of both the endocrine and exocrine pancreas was perfectly preserved. Pancreatic juice had remarkably few adverse effects on the recipient's urinary tract. Obstruction of the exocrine secretion induced atrophy of the acinar cells, proliferation of small pancreatic ducts, and a typical fragmentation of the islets of Langerhans. Prolamine was biologically degraded within 28 days. Following free intraperitoneal drainage, spontaneous suppression of the exocrine graft function occurred early after transplantation. Metabolic signs of diabetes mellitus including hypoinsulinemia, hyperglycemia, polydipsia, polyuria, and impaired glucose tolerance were completely normalized by pancreas transplantation irrespective of the surgical technique used. Despite fundamental differences in graft architecture no alteration of endocrine graft function was noted following vascularized pancreas transplantation by different surgical techniques.
The significance of portal venous drainage after whole-pancreas transplantation both for metabolic control and development of diabetic nephropathy was investigated. Streptozotocin-diabetic inbred LEW rats received a duct-ligated pancreas graft with either systemic or portal venous drainage and were followed for up to one year. Normal and untreated diabetic rats (n=18 in each group) served as controls. Irrespective of the route of venous drainage pancreas transplants normalized the diabetic polyuria, polyphagia, and polydipsia. Growth rates and general health did not differ from normal rats. Pancreas transplantation with portal venous drainage furthermore normalized nonfasting blood glucose and peripheral insulin levels, and intravenous glucose tolerance. Pancreas transplantation with systemic venous drainage, however, was associated with peripheral hyperinsulinemia, slightly elevated nonfasting blood glucose levels, and supranormal K-values in intravenous glucose tolerance tests. Though portal venous drainage was associated with better metabolic control than systemic venous drainage, both techniques of pancreas transplantation proved equally effective to prevent the development of diabetic glomerular membrane thickening determined 6 and 12 months posttransplant.
The course of acute rejection of major histocompatibility complex (MHC)-incompatible isolated rat pancreatic islets transplanted under the kidney capsule was monitored functionally and histologically from day 1 to 10. The patterns observed were compared to those of vascularized whole-pancreas transplants with preserved and suppressed exocrine secretion. In addition the morphologic reactions after isogenic transplantation of islets or whole-pancreas transplants are described. The sequential patterns of acute rejection were found to be essentially identical in isolated islet and whole-pancreas allografts. This was also true for the process of I-A-like class II MHC antigen induction. Endocrine cell necrosis and reduced insulin content of beta cells were detected in isolated islets but not in whole-organ isografts. Thus ischemic damage may have occurred to be transplanted islets on days 1 and 2 because connections to the renal vasculature were not demonstrated before day 3. Islet cell loss was, however, functionally compensated by beta cell proliferation beginning on day 4. From the first day after transplantation, an altered spacial distribution of insulin- and glucagon-containing cells was present in islet isografts. This phenomenon was, however, not unique to islets, but also occurred in duct-ligated whole-organ isografts on days 6 to 10.
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A new method for the performance of a hepatic transplantation in spite of a low portal blood flow situation is described casuistically. In a 36-year-old-patient suffering from liver cirrhosis due to hepatitis B, the portal blood system of the right and left liver parts were divided, the left part was perfused with a low flow of portal blood, the right one with arterialized caval blood. The function of the transplanted liver and the early postoperative course were excellent. During the further postoperative course portal perfusion presumably diminished or stopped on the left side from three weeks and on the right side from two months postoperatively. Nevertheless the general condition of the patient improved continuously; transient elevations of transaminases may reflect the disturbance of portal perfusion. The technique of this arterialized caval blood perfusion of the portal system is presumably applicable also for situations, in which there is no portal blood flow available for perfusion of a liver graft. Thus, the absence of possibility for reconstruction of portal blood inflow or a situation with a hypoplastic portal vein may no longer be considered as a technical contraindication for liver grafting.
We investigated the genetic control of heterotopic heart allograft rejection using a family of standard inbred, major histocompatibility complex (MHC)-congenic, and intra-MHC recombinant rat strains. Gene products of the various regions within the rat MHC differed markedly in their capacity to induce rejection. Isolated incompatibility at class I antigens encoded by the RTl.A and RTl.C regions failed to induce rejection within the observation period of 100 days, whereas class II antigens encoded by the RTl.B/D region provoked rapid rejection within 10 days. By comparison of the rejection times of isolated and combined incompatibilities a number of functional interactions could be demonstrated between individual MHC regions which either prolonged or shortened allograft survival. In contrast to rapid rejection of MHC-mismatched heart allografts, differences at non-MHC histocompatibility antigens were associated with graft survival beyond 100 days, although chronic rejection of variable severity was detected histologically. Disparity at non-MHC plus class I antigens, however, provoked acute heart allograft rejection.
A detailed survey of the microsurgical techniques of vascularized pancreas transplantation in streptozotocin-diabetic rats is presented, based on the experience of 1450 transplants. Various techniques were employed to manage exocrine graft secretion. These included enteric, urinary, and free intraperitoneal drainage, as well as duct ligation and obstruction. In addition to general complications, such as anesthetic deaths, afterbleeding, and infection, a number of specific surgical complications, including graft pancreatitis, acute venous thrombosis, and hypoglycemia, occurred. The overall success rate of pancreas transplantation was 83.9%. Incidence, causes, and possible prophylaxis of early and late postoperative complications are discussed in detail.