Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes.
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Pancreas transplantation in patients with type 1 diabetes presents allogeneic beta-cell autoantigens to the immune system long after the initial beta-cell destruction that leads to diabetes has occurred. The aims of this study were to determine whether re-exposure to beta-cell autoantigen through transplantation affect the humoral autoimmune response and whether its modulation correlates with graft outcome. Antibodies to the major autoantigens GAD (GADA) and protein tyrosine phosphatase IA-2 (IA-2A) were measured before and after transplantation in patients with type 1 diabetes who received pancreas and kidney allografts. In the 110 cases studied, pancreas graft survival was not significantly associated with the presence of GADA or IA-2A before transplantation. In the 75 patients with sequential follow-up samples up to 11.2 years after transplantation, autoantibodies were persistently undetectable in 44 cases (59%) and remained at stable detectable levels in 13 cases (17%). Substantial changes in antibody levels were found in 18 cases (24%), of which 13 cases (17%) had declining levels and 5 cases (7%) had marked increments after transplantation. Rising GADA and IA-2A levels in these five patients were predominantly of the IgG1 subclass, with progressive spreading of epitope reactivity. Pancreas graft function was lost 0.7-2.3 years after rising autoantibody levels in four of these five patients, and a significantly lower pancreas graft survival was found in patients with major rises in either GADA or IA-2A levels (P < 0.0001 vs. the remainder) and in patients having persistently high levels of IA-2A (P = 0.002 vs. stable antibody-negative patients). Kidney graft survival was not associated with islet autoantibody status. In conclusion, a minority of patients receiving pancreas allografts under generalized immunosuppression show a stimulation of islet autoantibody reactivity characteristic of that found in preclinical type 1 diabetes, which is almost invariably followed by graft function failure and resumption of insulin therapy. (+info)
Stabilisation of diabetic retinopathy following simultaneous pancreas and kidney transplant.
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BACKGROUND/AIMS: Simultaneous pancreas and kidney transplantation (SPK) has become an important option in selected IDDM patients with end stage renal disease (ESRD). Successful SPK transplants are associated with long term normoglycaemic control and improved quality of life. However, debate still continues on the benefit to patients in terms of stabilisation or amelioration of diabetic retinopathy. The progression of diabetic retinopathy (DR) in a cohort of 20 SPK transplant patients is reported. METHODS: All patients were reviewed postoperatively with corrected visual acuity, slit lamp examination, and fundal biomicroscopy. Preoperative data were collected retrospectively and DR was considered unstable if there had been a drop in Snellen acuity greater than three lines or a need for laser photocoagulation or vitrectomy in the 2 years preoperatively. RESULTS: 20 patients who received SPK transplants between March 1983 and April 1994 were reviewed (mean age 35.1 years; mean duration of IDDM = 24.6 years). 17 patients still had functioning grafts at a mean follow up of 5.1 years. Nine of these patients had unstable DR before transplantation. Of these, 89% (8/9) had stabilised DR following transplantation with only a single case requiring laser photocoagulation. Of the eight patients that had stable DR before transplantation all had stable DR following transplantation. 41% of cases (7/17) required cataract surgery during the follow up period. CONCLUSIONS: Advanced diabetic retinopathy is present in a high proportion of cases managed with SPK transplant as a consequence of the duration of IDDM and the presence of ESRD. More than 90% of cases have stable DR following transplant. (+info)
Evidence of recurrent type I diabetes following HLA-mismatched pancreas transplantation.
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Type 1 diabetes mellitus is considered as an autoimmune disease against beta cells. Diabetes recurrence after pancreas transplantation is well known in HLA-identical twins while it is rarely reported in recipients of cadaveric pancreatic grafts. In the present case report, diabetes recurrence occurred in a recipient who underwent cadaveric combined pancreas kidney transplantation. Seven years after transplantation the patient exhibited progressive hyperglycemia needing insulin therapy while the renal graft was well functioning. The diagnosis of recurrent disease was obtained on the histological features such as selective loss of beta cells without clear signs of insulitis and on the presence of markers (GAD 65 and IA-2) for humoral autoimmunity. It is intriguing that, at the time of recurrence of type 1 diabetes, the patient had stopped steroids and azathioprine, while only cyclosporine was maintained as immunosuppressive treatment. Our case report underlines the relevance of studying the humoral autoimmune response directed to islet autoantigens in cadaveric pancreas allograft recipients. Furthermore, it suggests that an efficient immunosuppressive treatment after transplantation may be able to reduce the autoimmune response against the pancreatic allograft. (+info)
Long-term (>1 year) analyses of chimerism and tolerance in mixed allogeneic chimeric mice using normal mouse combinations.
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We examined the induction of tolerance using pancreas allografts over the long term (>1 year) in mice for the human application of mixed allogeneic bone marrow transplantation (BMT). T cell-depleted BM cells (BMCs) of C57BL/6 (B6) and C3H/He (C3H) mice were transplanted at various ratios into lethally irradiated B6 mice. The percentages of C3H cells in the chimeric mice gradually decreased, finally declining to only a small percentage, except when the ratio of donor to recipient BMCs was 100:1. However, despite the marked decreases in C3H-type cells, all the pancreas allografts of C3H mice were accepted when more than 1% C3H cells were detected in the peripheral blood. To examine the relationships between percentages of transplanted donor cells and acceptance of pancreas allografts, various percentages of donor and recipient BMCs (5% to 30%) were transplanted. It was found that more than 10% donor cells were necessary for the pancreas allografts to be accepted. In vitro assays for mixed lymphocyte reaction and generation of cytotoxic T-lymphocytes revealed that spleen cells in chimeric mice accepting pancreas allografts are tolerant to both host-type and donor-type major histocompatibility complex (MHC) determinants, but show a vigorous responsiveness to third-party MHC determinants. Since donor-type hemopoietic stem cells (HSCs) were detected in the BM and the liver of the chimeric mice, donor-derived HSCs and donor-derived hematolymphoid cells are responsible for the induction of tolerance. It should be noted that the percentage of donor-type HSCs is higher in the liver (6.2%) than in the BM (0.9%). (+info)
Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients.
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A total of 1,305 blood samples from 85 solid organ transplant (SOT) recipients and 25 stem cell transplant (SCT) recipients at risk for cytomegalovirus (CMV) infection were prospectively collected and tested using the shell vial assay (SVA) and a leukocytic qualitative PCR (q-PCR). Of these, 462 specimens were further tested by direct quantification of CMV antigenemia by flow cytometry (FC-Ag), 125 were tested with a quantitative competitive PCR, and 200 were tested for pp65 antigenemia using the slide method (S-Ag). Laboratory data were statistically analyzed according to the presence of CMV-related symptoms. In SOT and SCT recipients, active CMV infection occurred in 63.5 and 36%, respectively, and CMV disease occurred in 53 and 24%, respectively. FC-Ag results correlated better with q-PCR and S-Ag than with SVA. The first test found to be positive during follow-up was FC-Ag in 73% of cases. In SOT recipients, FC-Ag showed the highest sensitivity and negative predictive value for the diagnosis of any grade of CMV disease. For FC-Ag, the threshold beyond which CMV disease was highly probable seemed to lie at 0.20% positive polymorphonuclear leukocytes. FC-Ag appears to be a useful test for the early detection of CMV infection and the prediction of CMV disease. (+info)
Kidney allograft outcome in simultaneous pancreas-kidney transplantation.
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BACKGROUND: In simultaneous pancreas-kidney transplantation, with both organs coming from the same donor, the addition of a pancreas to the kidney transplant does not jeopardize the kidney allograft outcome despite higher postoperative SPK morbidity. Pancreas allograft outcome has recently improved due to better organ selection and more accurate surgical techniques. OBJECTIVE: To demonstrate the positive impact of SPK on kidney allograft outcome versus kidney transplantation alone in insulin-dependent diabetes mellitus patients with end-stage renal failure. METHODS: We performed 39 consecutive SPKs in 14 female and 25 male IDDM patients with renal failure after an average waiting time of 9 months. Multi-organ donor age was 30 years (range 12-53). The kidneys were transplanted in the left retroperitoneal iliac fossa following completion of the pancreas transplantation; kidney cold ischemia time was 16 +/- 4 hours. Induction anti-rejection therapy was achieved with polyclonal antithymocytic globulin and methylprednisolone, and maintenance immunosuppression by triple drug therapy (prednisone, cyclosporine or tacrolimus, and azathioprine or mycophenolate mofetil). Infection and rejection were closely monitored. RESULTS: All kidney allografts produced immediate urinary output following SPK. Two renal grafts had mild function impairment due to acute tubular damage but recovered after a short delay. Three patients died from myocardial infarction, cerebrovascular event and abdominal sepsis on days 1, 32 and 45 respectively (1 year patient survival 92%). An additional kidney allograft was lost due to a renal artery pseudo-aneurysm requiring nephrectomy on day 26. Nineteen patients (49%) had an early rejection of the kidney that was resistant to pulse-steroid therapy in 6. No kidney graft was lost due to rejection. Patients with acute kidney-pancreas rejection episodes suffered from severe infection, which was the main cause of morbidity with a 55% re-admission rate. Complications of the pancreas allograft included graft pancreatitis and sepsis, leading to a poor kidney outcome with sub-optimal kidney function at 1 year. Kidney graft survival at one year was 89% or 95% after censoring the data for patients who died with functioning grafts. CONCLUSIONS: Eligible IDDM patients with advanced diabetic nephropathy should choose SPK over kidney transplantation alone from either a cadaver or a living source. (+info)
Expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells.
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Cell-cell and cell-matrix interactions play a critical role in tissue morphogenesis and in homeostasis of adult tissues. The integrin family of adhesion receptors regulates cellular interactions with the extracellular matrix, which provides three-dimensional information for tissue organization. It is currently thought that pancreatic islet cells develop from undifferentiated progenitors residing within the ductal epithelium of the fetal pancreas. This process involves cell budding from the duct, migration into the surrounding mesenchyme, differentiation, and clustering into the highly organized islet of Langerhans. Here we report that alpha(v)beta(3) and alpha(v)beta(5), two integrins known to coordinate epithelial cell adhesion and movement, are expressed in pancreatic ductal cells and clusters of undifferentiated cells emerging from the ductal epithelium. We show that expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins are developmentally regulated during pancreatic islet ontogeny, and mediate adhesion and migration of putative endocrine progenitor cells both in vitro and in vivo in a model of pancreatic islet development. Moreover, we demonstrate the expression of fibronectin and collagen IV in the basal membrane of pancreatic ducts and of cell clusters budding from the ductal epithelium. Conversely, expression of vitronectin marks a population of epithelial cells adjacent to, or emerging from, pancreatic ducts. Thus, these data provide the first evidence for the contribution of integrins alpha(v)beta(3) and alpha(v)beta(5) and their ligands to morphogenetic events in the human endocrine pancreas. (+info)
Long term studies of pancreas transplantation in experimental diabetes mellitus.
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Alloxan diabetes was induced in inbred rats that then were divided into four groups consisting of unoperated diabetic controls, sham-operated diabetic controls, rats given pancreaticoduodenal isografts, and rats given duct-ligated pancreas isografts. The animals were studied for from 18 months (controls) to two years (transplants) and the following important results were obtained: 1) In striking contrast to the diabetic controls, pancreas transplants of both types produced immediate and permanent relief of hyperglycemia, immediate and lasting elevation of serum insulin levels, a normal weight and growth curve, and good health for two years. Removal of the graft was followed by recurrence of severe diabetes. 2) Pancreas transplants of both types prevented the widespread and severe renal, ophthalmic and neural lesions of diabetes that were found in the diabetic controls. 3) The duct-ligated pancreas graft and pancreaticoduodenal transplant were equally effective in controlling diabetes. Ligation of the pancreatic duct was not followed by significant morphologic or clinical evidence of pancreatitis or by loss of endocrine function. 4) Portal venous drainage of the pancreas transplant was unnecessary for good endocrine function. (+info)