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Biomedical subjects

K L Brayman

Publications and source records attributed to K L Brayman.

At least 73 records · Page 4Linked to original sources
PubMed1992

Evaluation of intrathymic islet transplantation in the prediabetic period.

BACKGROUND: Beta-cell destruction in type I diabetes mellitus results from a chronic autoimmune process. Exposure of thymic T cells to islet antigens during the prehyperglycemic phase of diabetes may alter the likelihood of autoimmune damage to beta cells in the native pancreas. Thus we evaluated whether prophylactic major histocompatibility complex (MHC)-incompatible intrathymic islet allografts could prevent hyperglycemia and native pancreatic beta-cell destruction. METHODS: At 4 to 6 weeks of age, diabetes-prone BioBreeding rats received intrathymic injection of 1500 to 2000 noncultured MHC-incompatible Lewis islets. No immunosuppression was administered. Age-matched littermates underwent intrathymic injection of saline solution. RESULTS: None of 13 BioBreeding rat recipients of prophylactic intrathymic Lewis islet allografts became hyperglycemic versus 13 of 13 control rats (p less than 0.001). The age at onset of diabetes in the control group ranged from 77 to 104 days (mean, 86 days). Normoglycemia in recipients of intrathymic islet allografts persisted for greater than 8 months after transplantation, and thymectomy (graft removal) did not precipitate hyperglycemia. CONCLUSIONS: Prophylactic intrathymic MHC-incompatible islet allografts effectively prevent hyperglycemia and native beta-cell destruction in an animal model of autoimmune diabetes. Rejection and autoimmune destruction of intrathymic MHC-incompatible islet allografts were not seen after transplantation in the prediabetic (prehyperglycemic) period. Intrathymic islet allografts at an early age (before puberty) preserve native beta-cell function and may prevent or retard thymic atrophy.

Animals↗
PubMed1991

Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

Acyclovir↗
PubMed1991

Long-term metabolic function of pancreas transplants and influence of rejection episodes.

Pancreas grafts, when not rejected, can sustain an insulin-independent state in type I diabetic recipients for indefinite periods. To what extent the metabolic control achieved approaches that of normal individuals, the relationships between graft endocrine and exocrine function, the effect of reversible rejection episodes on subsequent graft function, and the correlation between the results of serial tests of graft function were determined by studies at 1 month, 1 year, and 2 years in a cohort of 39 recipients (29 females, 10 males; mean age (+/- SD), 33 +/- 5 years; mean duration of diabetes, 22 +/- 6 years) of bladder-drained pancreas transplants performed between November 1984 and December 1988. Fifteen patients received a pancreas transplant alone, 8 a pancreas after a kidney, and 16 a simultaneous pancreas/kidney transplant. Graft endocrine function was tested by a 24-hr metabolic profile of blood glucose levels before meals, at 1 and 2 hr after meals, and during the night (14 values in all), by intravenous and oral blood glucose tolerance tests, and by glycosylated hemoglobin levels (HA1 and HA1c). Graft exocrine function was assessed by urine amylase activity (U/hr). The results of the tests in the recipients were subjected to paired comparisons between timepoints and at each timepoint to the results of the same tests in 55 normal nondiabetic control individuals. The means of the mean 24-hr profile glucose (mg/dl) values were significantly lower (P less than 0.05) at 1 and 2 years posttransplant (116 +/- 27 and 115 +/- 15, respectively) than at 1 month (128 +/- 31) in the recipients, but the mean of the mean values in the normal controls (100 +/- 7) was even lower (P less than 0.05). Mean values of individual timepoints during the profile were significantly lower for 6 of the 14 values in the controls than in the recipients. The mean IVGTT K value of the normal controls (-1.9 +/- 0.4%) was significantly lower than the 1-month and 2-year values of the recipients (-1.5 +/- 0.5% and -1.3 +/- 0.6%, respectively), but the comparison with the 1-year value (-1.6 +/- 0.6%) was not significant. The mean glucose levels at zero minutes and between 120 and 300 min of the OGTTs were significantly lower at both 1 and 2 years than at 1 month in the recipients, and the values in the control group were also significantly lower than in the recipients at 1 month but not at 1 and 2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Glucose↗
PubMed1991

Major-histocompatibility-complex restricted and nonrestricted autoimmune effector mechanisms in BB rats.

To investigate whether the immunologic mechanisms of autoimmune pancreatic beta-cell destruction are MHC restricted, we examined the relative vulnerability of islet allografts from a panel of MHC-compatible and -incompatible donors to autoimmune damage after transplantation to spontaneously diabetic BB recipients. To circumvent a potentially confounding allograft response to the foreign islet graft, we utilized two strategies: (1) pretransplant in vitro culture of islets to delete intraislet APCs; and (2) induction of islet donor-specific immunologic tolerance in diabetes-prone BB rats. Experiments employing organ culture to prevent rejection demonstrated that MHC-incompatible grafts were significantly less vulnerable to autoimmunity than MHC-compatible grafts. In contrast, when we used the model of immunologic tolerance to exclude rejection, both MHC-compatible and -incompatible islet grafts were equally susceptible to autoimmune damage. The reason for this discrepancy has not been defined fully but may be related to our observation that tolerant BB animals exhibit increased peripheral blood NK-cell activity. NK cells are known to be cytotoxic to islets in vitro and could play a role in a non-MHC-restricted diabetogenic response in vivo. We conclude that both MHC-restricted and nonrestricted mechanisms are capable of contributing to anti-beta-cell autoimmunity in BB rats.

Animals↗
PubMed1990

The organ donor.

Vascularized organ transplantation is now a widely applied therapy for patients with end-stage diseases of the heart, lungs, liver, kidneys, and pancreas. A critical shortage of donor organs exists in the United States and, as a consequence, prospective transplant recipients die while waiting for a life-saving transplant. The apparent shortage of cadaver organs is, in large part, caused by the reluctance and failure of the physician and the public to promote cadaver organ donation. Educational awareness programs for both professional personnel and the public at large are needed to increase the number of potential donors and multiorgan procurements carried out. All victims of trauma with severe closed head injury or cerebrovascular catastrophe secondary to anoxia should be considered as potential organ donors and referred to the local organ procurement agency for evaluation.

Aged↗
PubMed1989

Prevention of recurrent diabetes in BB rats after islet transplantation by monoclonal antibody therapy.

Two immune responses imperil pancreatic islet allografts transplanted into subjects afflicted with autoimmune diabetes: 1) the well-described allograft response that is mounted against tissues bearing foreign transplantation antigens and 2) a recurrence of the beta-cell-specific autoimmune process responsible for the primary disease. To define the role of autoimmune response to transplanted islets, the possibility of a rejection response must be prevented. To accomplish this in spontaneously diabetic BB rats, we induced neonatal tolerance. We found that recurrent autoimmunity in tolerant BB rats can be prevented by treatment of recipients with the monoclonal antibody OX8 (specific for cytotoxic T-lymphocytes) but not W3/25 (specific for helper T-lymphocytes). These findings provide direct evidence for the role of OX8-bearing lymphocytes in autoimmune diabetogenesis.

Animals↗
PubMed1988

Prophylaxis of serious cytomegalovirus infection in renal transplant candidates using live human cytomegalovirus vaccine. Interim results of a randomized controlled trial.

We report the interim results of a randomized, double-blind, placebo-controlled, clinical trial of prophylactic, live, attenuated cytomegalovirus (CMV) vaccination (Towne strain of CMV) of renal transplant candidates (RTCs). One hundred seventy-two RTCs were treated and subsequently underwent transplantation and followed up for at least one year and up to five years after transplantation. Eighty-eight RTCs received vaccine, and 84 received placebo. Results were analyzed according to the prevaccination serologic status (anti-CMV antibody titer) of the recipient (R- or R+) and the donor (D- or D+). The overall incidence of CMV disease was highest in the R-D+ group and almost absent in the R-D- group. There was no difference in the incidence of CMV infection or disease between vaccinated and respective placebo control recipients in either the R-D+, R+D+, R+D-, or R-D- groups. In contrast, the severity of CMV disease was significantly decreased in R-D+ vaccinees vs R-D+ placebo-treated recipients. Moreover, in the R-D+ group, one- and five-year cadaver renal allograft actuarial survival rates were 73% and 62%, respectively, for CMV vaccinees vs 40% and 25%, respectively, for control placebo patients. We conclude that seronegative cadaver RTCs may benefit from vaccination with live, attenuated, Towne strain CMV vaccine before transplantation.

Adult↗
PubMed1988

Prevention of recurrent autoimmune diabetes in BB rats by anti-asialo-GM1 antibody.

BB rats exhibit a syndrome of spontaneous diabetes that has clinical and pathological characteristics analogous to those found in human insulin-dependent diabetes mellitus (IDDM). Islet tissue transplanted into spontaneously diabetic BB rats is uniformly destroyed by a recurrence of the autoimmune response that destroyed the diabetic subject's native islets. To examine recurrent autoimmune destruction of transplanted islets, it is necessary to exclude islet damage that might result from allograft rejection. We utilized neonatal tolerance induction to prevent rejection of Wistar-Furth (WF) (RT1u) islet allografts by spontaneously diabetic BB recipients. We determined that islet-recipient treatment with anti-asialo-GM1 (anti-AGM1) antibody prevents recurrent autoimmune diabetes that would otherwise destroy transplanted WF islet grafts. Anti-AGM1 therapy significantly decreased peripheral blood natural killer (NK) cell activity. These data suggest a role for NK cells in the pathogenesis of recurrent diabetes in neonatally tolerant BB rats.

Animals↗
PubMed1988

Immunoprediction of diabetes and evaluation of pancreatic islet transplantation during the prediabetic period.

The autoimmune diabetic syndrome of the biobreeding (BB) rat currently constitutes the best animal model for human type I diabetes. Since prediction of human beings at high risk for development of diabetes by immunologic and physiologic parameters is not possible at present, we investigated the feasibility of immunoprediction of diabetes in normoglycemic BB diabetes-prone (BBdp) rats. Peripheral blood lymphocyte counts (PBLC) accurately predicted future development of diabetes in a cohort of 50 BBdp rats (100% specificity, 95.8% sensitivity for PBLC less than 3800/mm3). We also assessed the fate of normal islets transplanted from MHC-compatible non-diabetes-prone Wistar Furth (WF) donors in the prediabetic milieu of BBdp hosts that were known on the basis of their PBLC destined either to become diabetic or to remain normoglycemic. In 13 BBdp rats in which diabetes was predicted the native pancreatic beta cells were eliminated at 35 days of age with streptozocin and replaced with transplanted WF islets. Neonatally induced tolerance of WF antigens prevented rejection. After successful islet transplantation, spontaneous diabetes occurred in 100% (5/5) of the rats in which the development of diabetes was predicted. The identical protocol in eight rats predicted not to have diabetes resulted in permanent normoglycemia in all. We conclude that normal islets are susceptible to anti-islet autoimmunity after transplantation in the prediabetic period.

Animals↗