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Recovery from diabetes was observed in streptozotocin-treated mice that received subcutaneous, isogeneic transplants of duct-ligated pancreas. Transplants excised from recovered hosts contained both immunoreactive insulin (IRI) and glucagon (IRG), indicating that both A and B cells capable of hormone storage were present. The IRI content in transplants, although only one sixth of that transplanted 6 wk earlier, was still 21/2 times greater than that in the host pancreas and was inversely related to the plasma glucose of the recipient during and after recovery. The IRI content in the transplant added to that in the host pancreas totaled 13% of the IRI found in the normal mouse pancreas, which sufficed for over-all recovery from diabetes but was insufficient to provide normal glucose tolerance and insulin response to a major glucose challenge. The abnormally high content of glucagon noted in the pancreas of hyperglycemic, sham transplanted mice was reduced by one-half in the pancreas of those transplanted mice returning to normal plasma glucose and insulin. Thus, the insulin content of the transplant was important to the recovery of isografted mice, but in addition, and perhaps as a consequence of recovery, there was a slight increase in the insulin storage capacity of the host pancreas and a marked reduction of glucagon compared to the content of these hormones in the pancreas of hyperglycemic, sham transplanted mice.
BACKGROUND: Rejection after pancreas-kidney transplantation may occur isolated or concurrently in both grafts. To get more insight into the cellular mechanisms underlying these rejection episodes, we compared the functional characteristics of pancreas and kidney graft-infiltrating T cells. METHODS: Graft-infiltrating T cell (GIC) lines were cultured from simultaneously taken pancreas and kidney biopsies from eight patients. CD4 to CD8 ratios were determined by fluorescence-activated cell sorter and cytotoxicity toward donor proximal tubular epithelial cells (PTEC) and donor spleen cells (DSC) using a standard cytotoxicity assay. Cytokine production was determined by enzyme-linked immunosorbent assay. RESULTS: CD4 to CD8 ratios were comparable between the pancreas and kidney lines for each patient, but differences were observed in cytotoxicity toward PTEC and DSC. For four of eight patients, the lysis of PTEC by pancreas GIC was less than the lysis induced by kidney GIC. This was also seen in three of five patients for lysis of DSC. The specificity of GIC lines toward mismatched donor antigens was studied for two patients and appeared to be comparable for pancreas and kidney. Most GIC lines produced interferon (IFN)-gamma (75.5+/-22.7 pg/ml), but no IL-10, indicating that the cell lines consisted primarily of Th1 and type 1 CD8+ cells. Mean production of IL-6 was 465.6+/-193.6 pg/ml. No major differences were observed between kidney and pancreas GIC for either cytokine. CONCLUSIONS: We conclude that pancreas and kidney GIC lines have the same phenotype, cytokine production, and allospecificity. Differences were, however, seen for lysis of PTEC and DSC, suggesting that tissue-specific antigens might play a role.
A multivariate analysis of prognostic factors for graft failure was performed on patients in the International Pancreas Transplant Registry. The analysis was restricted to the period January 1978 to June 1987 and included 764 patients. All patients had at least 1 year of follow-up. The following variables were studied: transplant year, continent (N. America, Europe, others), type of donor (cadaver, living related mismatched, living related HLA-identical), donor mismatch at the HLA A, B loci, donor mismatch at the DR loci, preservation time, kidney association (pancreas transplant alone, simultaneous pancreas and kidney transplant, pancreas after kidney transplant), whole versus segmental pancreatic transplant, graft duct management technique (polymer injection, enteric drainage, stomach drainage, bladder drainage), and immunosuppression. By stepwise, logistic regression analysis, we found that the following factors were predictive for 1-year graft function: donor mismatch at the DR loci (P = 0.0003), kidney association (P less than 0.0001), type of donor (P = 0.04), and immunosuppression (P = 0.0002). For donor mismatch at the DR loci, we found an odds ratio for success of 2.2 for 0 versus 2 mismatches. The odds for success were 2.9 for simultaneous pancreas and kidney transplant versus pancreas transplant alone. The best results--79% 1-year graft survival--were obtained for the combination of 0 mismatches at the DR loci, pancreas after kidney transplant, living related HLA-identical donor, and the immunosuppressive regimen consisting of cyclosporin, azathioprine, and prednisone. Patients receiving a pancreas transplant alone with 0 mismatches at the DR loci, living related HLA-identical donor, and triple immunosuppressive regimen had a predicted 1-year graft survival of 71%.
A carcinoma in the dorsal part of the pancreas divisum with an annular pancreas in the anterior part is reported. A 79-yr-old female was admitted in our hospital complaining of epigastralgia. Computed tomography (CT) and ultrasound (US) showed an irregular mass in the pancreatic body. A pancreatogram obtained through the major duodenal papilla demonstrated only the ventral pancreatic duct that encircled the duodenum. Contrast medium injected from the minor duodenal papilla showed Santorini's duct obstruction at the neck portion of the pancreas without communication with the ventral pancreatic duct. The patient died with liver metastases. Autopsy confirmed annular pancreas and a 6-cm tumor in the pancreatic body extending to the pancreatic head and pancreas divisum. Pancreatic carcinoma; histologically a moderately differentiated adenocarcinoma; originated from the dorsal part of pancreas divisum. To our knowledge this is the first report of pancreatic carcinoma associated with annular pancreas coexistent with pancreas divisum.
BACKGROUND: Gender differences in graft survival has been reported after some types of organ transplantation, but not after pancreas transplantation. This study compares graft survival between women and men after simultaneous pancreas-kidney transplantation (SPK). METHODS: All first time SPK (n = 163) transplants (109 M/54 F) performed between 1989 and 2000 at University of Nebraska Medical Center, where data was available, were analyzed for overall graft and patient survival. Graft failure was then subdivided into early (<6 months), and late (>6 months), and compared between women and men. RESULTS: The 5-yr pancreas and kidney graft survival rates for all SPK recipients was 86% [95% confidence interval (CI) = 81-92%] and 87% (95% CI = 82-93%), respectively. While overall pancreas graft survival in women was similar to men (p = 0.16), early pancreas graft failure was greater in women than men (p = 0.010) with no one cause for failure predominant. There was no gender difference in late pancreas graft failure or in early, or late kidney graft failure in the same recipients. The gender difference was unexplained by differences in age, immunosuppression, body mass index (BMI), or diabetes duration between women and men. CONCLUSIONS: This is the first report of a gender difference in pancreas graft survival after SPK with greater early (<6 months) pancreas graft failure in women than men. With no gender difference in kidney graft failure in the same individuals, gender differences in immune responses are unlikely to be the cause. Multiple variables likely contribute.
The regulatory DNA (enhancer) of polyomavirus (Py) is a major determinant of tissue-specific DNA replication during acute infection of newborn mice. Previously, we reported that the combination of one of the two Py enhancers (A enhancer) and the repeated Moloney murine leukemia virus (Mo-MuLV) enhancer gave a chimeric Py genome (Py-MuLV) that replicates predominantly in the acinar cells of the pancreas, a tissue not permissive for wild-type PyA2 replication (R. Rochford, B. A. Campbell, and L. P. Villareal. Proc. Nat. Acad. Sci. USA 84:449-453,1987). In this report, we further examine the combined enhancer requirements for acinar cell-specific Py replication. We also compare enhancer requirements for Py replication in the acinar cells of the pancreas with those of a transformed acinar cell line (266-6 cells). The deletion of sequences within the A enhancer of Py-MuLV (nucleotides 5098 to 5132) results in a virus with 10-fold-reduced levels of pancreas-specific replication. The deletion, however, of one of the 72-bp repeated Mo-MuLV enhancer sequences from Py-MuLV results in a complete loss of pancreas-specific DNA replication. Thus, the Py A enhancer is required for efficient replication of Py in the pancreas without otherwise altering organ specificity, but both of the repeated copies of the Mo-MuLV enhancer are essential for pancreas-specific Py replication. In contrast to the enhancer requirements for in vivo pancreas replication, in transformed acinar cells (266-6), PyA2 wild-type replicated efficiently and the Py-MuLV recombinant replicated inefficiently. These data suggest that the cell-specific control of DNA replication is different between normal pancreas cells and their transformed cell line counterparts and that this difference is apparent in the enhancer requirement of cell-specific Py DNA replication.
Mammalian deoxyribonucleases I (DNase I) are classified into three types, namely, pancreas, parotid, and pancreas-parotid (mixed), based on differences in their tissue concentrations. In this study, DNase I purification by concanavalin A-wheat germ agglutinin mixture-agarose column from rat (parotid type), rabbit (mixed type), and pig (pancreas type) is described. This method permits a relatively easy one-step purification of DNase I from rat and rabbit parotid glands, the rat submaxillary gland, and porcine pancreas. To elucidate differences among the three types, these DNases I were subjected to enzymatic deglycosylation either by peptide N-glycosidase F (PNGase F) or endoglycosidase H (Endo H). Following deglycosylation, digests were separated on DNA-casting polyacrylamide gel electrophoresis. PNGase F produced a single lower mobility product in all samples. Endo H produced a double band in rat and rabbit parotid glands and porcine pancreas, and a single band in the rabbit pancreas corresponding with the PNGase F product. DNase I activity of the porcine pancreas was completely extinguished by deglycosylation, while that of the parotid glands and rabbit pancreas was unaffected. Our results suggest that the distinct properties of DNase I exhibited by the three types may be attributed to differences in the extent of post-translational N-linked glycosylation of the enzyme.
Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.
As of November 1997 more than 9,800 pancreas transplants had been reported to the IPTR, including more than 7,400 US and more than 2,400 non-US cases. Cases reported since the inception of UNOS in 1987 (more than 6,800 in the US and more than 2,000 from outside the US) were analyzed, with emphasis on 1994-97 cases. In the US, for all 1994-97 SPK transplants (n = 2,585), one-year patient, pancreas and kidney graft survival rates were 94%, 82% and 90%, respectively; for all PAK cases (n = 230), patient and graft survival rates at one year were 95% and 71%; and for all PTA cases (n = 117), patient and graft survival rates at one year were 93% and 62%, respectively. The 1994-97 pancreas survival rates in all categories were significantly higher than in previous eras. Analysis of bladder versus enteric drainage (BD vs ED) was made only for 1994-97 SPK cases since there were too few solitary ED cases for a comparison. One-year pancreas survival rates (all causes of failure included) were 83% for BD (n = 1,995) versus 80% for ED (n = 456) cases (p = NS). However, nearly 20% of SPK BD grafts had been converted to ED by 2 years. The pancreas retransplant success rates have also significantly increased over time. For 1994-97 pancreas retransplants (n = 92), the one-year graft survival rate was 72%. The technical failure (TF) rate for pancreas transplants has declined over time. For 1994-96 BD cases, the TF rate was 8% in SPK (n = 1,995), 13% in PAK (n = 174) and 11% in PTA (n = 90) cases. For SPK ED cases (n = 456) the TF rate was 11% (p = 0.06 vs SPK BD). The most common cause of technical loss was graft thrombosis, 5.5% for SPK, 10.2% for PAK and 6.7% for PTA. The TF rates were significantly higher in grafts from older (> 45 yrs) donors and donors who died from cardiovascular disease. The immunological graft loss rate has also significantly declined in all categories. For 1994-97, technically successful (TS) cases (DWFG censored), the rejection loss rate at one year was 2% in the SPK (n = 2,234), 9% in the PAK (n = 154), and 16% in the PTA (n = 78) categories. Cox multivariate analyses were done in each recipient category to assess for factors that influence risks of pancreas graft loss. Increasing donor age was a risk factor in all categories. HLA mismatching was important only in the solitary (PAK and PTA) categories. FK506 use was associated with a positive effect in all categories, as was MMF in the SPK category.
Cellular adhesion of sialyl-Lewis-a(SLea)-positive pancreas carcinoma to endothelial cells (EC) is augmented by activation of EC via up-regulated E-selectin expression on EC. Co-cultivation of pancreas-carcinoma cells, PCI-24, with human umbilical-vein endothelial cells (HUVEC) for 5 hr at the PCI-to-HUVEC ratio of 1:10 induced E-selectin expression on the endothelial-cell surface, augmenting SLea-positive pancreas-carcinoma cell attachment with HUVEC. Culture supernatants of 6 tested pancreas-carcinoma cell lines contained soluble, E-selectin-inducing factor(s). The E-selectin-inducing effect by the supernatants was blocked by the protein-kinase-C inhibitor, H7. Antibodies against SLea and E-selectin but not SLex or ICAM-1 blocked the increased pancreas-carcinoma-to-endothelial attachment. Paraformaldehyde(PFA)-fixed PCI-24 cells also induced E-selectin on vascular endothelial cells upon direct contact with endothelial cells, indicating the presence of a membrane-bound form. The 6 pancreas-carcinoma lines all produced IL-1 alpha mRNA and protein but not IL-1 beta or TNF-alpha protein and/or mRNA. Absorption of IL-1 alpha from the supernatants by IL-1 alpha-specific antibody almost completely abolished E-selectin-inducing activity. Anti-IL-1 alpha antibody also abolished the E-selectin-inducing activity of PFA-fixed PCI. IL-1 alpha production by PCI cells was up-regulated by TNF-alpha. These observations suggest that substance(s) produced by pancreas-carcinoma cells, in this case, IL-1 alpha, may contribute to pancreas-carcinoma-cell colonization in non-inflamed, distant locations in vivo, by activating vascular endothelial cells.
Cellular adhesion between sialyl Lewis a (SLea)-positive pancreas carcinoma and endothelial cells is augmented by exogenous cytokines such as interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha through an upregulated E-selectin expression on endothelial cells. Preincubation of pancreas carcinoma cells with endothelial cells for 4-6 hours at the ratio of 1:10 induced E-selectin expression on endothelial cell surface, and dramatically increased subsequent attachment of SLea-positive pancreas carcinoma with endothelial cells. Paraformaldehyde-fixed PCI cells also induced E-selectin on vascular endothelial cells upon direct contact with endothelial cells. Culture supernatants from all six pancreas carcinoma cell lines contained soluble, E-selectin-inducible factors. Antibodies against SLea and E-selectin but not SLex or ICAM-1 blocked the increased pancreas carcinoma-to-endothelial attachment. These findings suggested that SLea-positive pancreas carcinoma cells produced E-selectin-inducing cytokines, both in the soluble and the membrane bound forms, resulted in augmented attachment to endothelial cells in vitro. The soluble factor lost its activity to induce E-selectin at 70 degrees C, and was different from IL-1-beta or TNF-alpha, because the supernatants contained no measurable IL-1 beta and TNF-alpha. Moreover, pretreatment of the supernatants with specific antibodies to IL-1 beta and TNF-alpha could not neutralize the E-selectin-inducing activity. Instead, all six pancreas carcinoma cell lines produced proteins of IL-1 alpha, and preincubation of the supernatant with specific antibody to IL-1 alpha almost completely removed the E-selectin-inducing activity from the supernatants. The collecting evidence suggests that substances such as IL-1 alpha produced by pancreas carcinoma cells may contribute to hematogenous metastasis of cancers in non-inflamed distant locations.
OBJECTIVE: This study was designed to evaluate the results of solitary pancreas transplantation in a protocol that uses the new immunosuppressant tacrolimus (FK) and liberally applies ultrasound-guided percutaneous pancreas biopsy to diagnose rejection. SUMMARY BACKGROUND DATA: Pancreas graft survival in patients who simultaneously receive a kidney transplant (SPK) historically has been 75% to 90% at 1 year, approaching that of cadaveric kidney transplantations. In sharp contrast, graft survival rates in patients who receive a pancreas atone (PA) have remained static over the past decade, with approximately 50% functional at 1 year. It was hypothesized that the results of PA transplantations would improve with newer maintenance immunosuppressants and biopsy techniques. METHODS: Twenty-seven PA recipients prospectively were treated with FK-based immunosuppression (PA-FK). Percutaneous biopsy was performed for hyperamylasemia, hyperlipasemia, hypoamylasuria, or unexplained fever. One year pancreas graft survival in these patients was compared to 15 cyclosporine treated PA cases (PA-CsA) and 113 SPK recipients. RESULTS: The 1-year pancreas graft survival rate of 90.1% in technically successful PA-FK patients was significantly better than the 53.4% rate in PA-CsA recipients (p = 0.002) and no different than the 87.4% rate in SPK recipients. The only graft lost to acute rejection in the PA-FK group was because of acknowledged patient noncompliance. Percutaneous biopsy substantially improved the diagnostic certainty in cases of suspected rejection and was associated with a low complication rate (3/178 = 1.5%). CONCLUSIONS: Modern immunosuppression and biopsy techniques have improved the success of solitary pancreas transplantations to the point where outcome is now equivalent to that of SPKs.
Ectopic pancreas is a rare entity but the second most prevalent pancreatic anomaly. Heterotopic pancreas is defined as the presence of pancreatic tissue without any anatomic or vascular continuity with the main body of the pancreas. Its aetiology is not clearly established. In 1916, Poppi published for the first time evidence of heterotopic pancreas in the gallbladder. A review of the literature up to the present showed only 28 more cases worldwide of ectopic pancreas in the gallbladder. Aberrant pancreas is incidentally discovered in 2% of autopsies and has been estimated to occur once in every 500 upper abdominal explorations. Ninety per cent of ectopic pancreas is found in the stomach, duodenum, and jejunum. Mostly it is asymptomatic and benign. For this reason, therapy is indicated only in patients with symptoms such as pyloric obstruction, bleeding, and malignant transformation. Surgical resection or endoscopic mucosal resection as a newer method are recommended.