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Biomedical subjects

C F Barker

Publications and source records attributed to C F Barker.

At least 145 records · Page 8Linked to original sources
PubMed1987

Prevention of diabetes in BB rats by intermittent administration of cyclosporine.

The successful prevention of spontaneous autoimmune diabetes in biobreeding (BB) rats--the closest animal model to human type I diabetes mellitus--by daily administrations of cyclosporine (CsA) has prompted clinical trials of CsA immunosuppression in human diabetes. Although remissions from hyperglycemia have been achieved in human subjects, nephrotoxicity and recurrence of diabetes after discontinuation of CsA have been observed. Therefore we studied the biologic efficacy of intermittent administration of CsA, a theoretically less dangerous immunosuppressive protocol, in the prevention of spontaneous diabetes in the BB rat. Beginning at 30 to 49 or 50 to 55 days of age, treated animals (n = 86) received daily injections of CsA (15 mg/Kg) for 2 weeks (induction phase) and then twice weekly (maintenance phase) until 160 days of age. A third group of animals (n = 31) received daily CsA for 14 days only. Control littermates (n = 121) were not injected. All animals were followed to 275 days of age. Intermittent administration of CsA was determined to be a biologically effective regimen in the prevention of spontaneous diabetes in the BB rat. Blood levels of CsA and the major CsA metabolites were undetectable intermittently during the course of therapy. Major complications associated with CsA immunosuppression (nephrotoxicity, malignancy, and infection) were not associated with the intermittent CsA protocol. We conclude that spontaneous diabetes can be delayed and often permanently prevented by intermittent administration of CsA. This immunosuppressive regimen deserves further consideration as a biologically effective, but theoretically less toxic, therapeutic regimen.

Animals↗
PubMed1986

Adverse effect of splenectomy on the survival of patients with more than one kidney transplant.

Risk factors associated with death were identified in a cohort of patients who received 2 or more kidney transplants. Data on 19 variables were collected by chart review on 774 patients who received allografts between 1973 and 1980 at any one of 3 hospitals in Philadelphia. 124 of the patients received two or more transplants and were followed for a minimum of 1.5 years. Modified life table analyses of single variables indicated that 7 factors--splenectomy, donor source, age, transplant hospital, number of HLA mismatches, donor sex, and survival time of the prior graft--were significantly related to patient survival. Using all 19 variables, the proportional hazards model was fit to the data. The characteristics most related to survival were splenectomy (P less than .001), donor source (P = .0022), and age (P = .0015). The other 4 factors that were significant on univariate analysis were not significant in this multivariate analysis. The relative risk of death was 5.5 for patients who had had a splenectomy compared with those who had not had a splenectomy. Patients who had received more than one transplant were compared with patients who had received only one transplant, and a subset of recipients of primary transplants who returned to dialysis after primary graft failure. Survival of patients who had received one transplant was approximately the same as that of the retransplanted population. When the proportional hazards model was fit to the populations that received one transplant and compared with the model for the retransplanted group, only age and donor source were common to all three models. The effect of splenectomy on survival was significant for the total population of primary transplant recipients but had no effect on the survival of the subset of recipients whose kidney grafts had failed and were returned to hemodialysis. Infection accounted for 45% of the deaths among splenectomized, retransplanted patients. A higher percentage of septic deaths occurred in patients whose grafts were functioning at the time of death when compared with patients who had returned to dialysis after secondary graft failure. Although retransplantation alone is not associated with an increased mortality, retransplantation in splenectomized patients carries a high risk of death.

Adult↗
PubMed1986

Transplantation of cultured pancreatic islets to BB rats.

Pancreatic islets held in tissue culture before transplantation into artificially induced diabetics are not rejected. In animals and human identical twin transplants, the autoimmunity of naturally occurring diabetes may destroy islets, even if rejection is avoided. Therefore we studied whether autoimmune damage of islets can be avoided by pretransplant culture. Recipients were BB rats, which spontaneously developed diabetes. Donors were either Wistar Furth (WF) (major histocompatibility [MHC] identical to BB rats) or Lewis (MHC nonidentical to BB rats). Islets were inoculated into the portal vein either immediately after isolation or after 14 days in tissue culture (95% air, 5% CO2, 24 degrees C). Recipients of cultured islets received a single injection of 1 ml of antilymphocyte serum at the time of transplant. Recurrence of diabetes after transplantation of freshly isolated MHC incompatible Lewis islets occurred rapidly on the basis of rejection or autoimmune damage (or both). Precultured Lewis islets had prolonged or permanent survival. Freshly isolated MHC compatible WF islets were destroyed, and no improvement was seen with culture. We conclude that autoimmune destruction of transplanted islets can be avoided by tissue culture, as can rejection. This is important because this strategy is effective only if recipient and donor differ at the MHC locus. Islet donors may need to be selected on the basis of disparity of histocompatibility factors.

Animals↗
PubMed1985

Treatment of lymphocele in renal allograft recipients.

Retroperitoneal lymphoceles developed in 12 renal allograft recipients during the last nine years. The interval between transplantation and the development of symptoms averaged seven months. The specific syndrome suggesting the presence of a lymphocele included lower abdominal swelling, weight gain, and, occasionally, fever without an obvious source of infection. Although these symptoms mimicked allograft rejection, diagnosis was easily made by ultrasound and intravenous pyelogram. Surgical marsupialization of the lymphocele with drainage into the peritoneal cavity proved to be an effective treatment.

Adult↗
PubMed1985

The role of pretransplant immunity in protection from cytomegalovirus disease following renal transplantation.

To determine the extent to which pretransplant immunity resulting from natural infection protects against cytomegalovirus (CMV) disease, we analyzed CMV serology on 153 kidney donor and recipient pairs and followed transplant patients to determine incidence and severity of CMV disease. The overall incidence of CMV disease was 22%. Significant differences occurred in CMV disease incidence and severity, depending on the immune status of the kidney donor and recipient. Among recipients of kidneys from seropositive donors, immunity offered significant protection from CMV disease, reducing its incidence from 61% in nonimmune to 24% in immune patients (P less than 0.01). Pretransplant immune patients also had fever CMV-related complications. Among recipients of kidneys from seronegative donors, pretransplant immunity conferred a significant risk of CMV disease; immune patients had a 20% incidence of CMV disease compared with 2% in nonimmune patients (P less than 0.02). Disease was generally mild in all patients receiving kidneys from CMV infection had a 3-fold higher incidence of CMV disease than patients with reactivation infection (P less than 0.01). The incidence of CMV disease was similar in immune patients, whether they received a kidney from a seropositive or a seronegative donor. However, an important observation was that disease was significantly more severe in immune patients receiving a kidney from a seropositive donor (P less than 0.05). This indicates that if kidneys from seropositive donors are selected for use only in seropositive recipients, this places the immune patient at a higher risk for severe CMV disease. We conclude that pretransplant immunity offers a significant advantage to patients receiving kidneys from seropositive donors.

Adolescent↗
PubMed1985

Immunologic studies of the prediabetic stage in the spontaneous autoimmune diabetes mellitus of the BB rat.

Twenty-eight BB diabetes-prone rats underwent prospective analysis to determine levels of circulating Ia antigen-bearing "activated" T lymphocytes prior to 50 days of age using mouse antirat monoclonal antibodies OX6 (anti-Ia) and W3/13 (anti-T-cell) and a fluorescence-activated cell sorter. Pancreatic biopsies were obtained within 48 hrs of lymphocyte sampling and histologically examined for the presence of a lymphocytic infiltrate. Elevated levels of "activated" T lymphocytes (above 4.00%) accurately identified a prediabetic stage and predicted which BB rats would subsequently become diabetic (93% sensitivity). The insulitis lesion occurs in the latter portion of this immunologically defined prediabetic stage just prior to the development of hyperglycemia. This observation suggests that islet cell destruction represents the final focus of a chronic immune response.

Animals↗
PubMed1985

The influence of T-lymphocyte precursor cells and thymus grafts on the cellular immunodeficiencies of the BB rat.

To determine whether abnormal T-lymphocyte precursor cells or an abnormal thymus is responsible for the immunologic deficiencies of spontaneously diabetic BB rats, thymus grafts or T-cell-depleted bone marrow cells were exchanged between diabetes-prone and non-diabetes-prone animals. Analysis of peripheral lymphocyte populations from these recipients with monoclonal antibodies, a fluorescence activated cell sorter, and mixed lymphocyte culture tests indicate that an abnormal thymus is not responsible for the immunodeficiency of BB rats, but that the defect resides within the lymphocyte precursor pool.

Animals↗
PubMed1985

"Activated" T-lymphocyte levels in the spontaneously diabetic BB rat syndrome.

About 50% of individual members of a diabetes-prone stock of BB rats eventually become hyperglycemic (usually between 60 and 180 days of age) while the remainder remain normoglycemic for life. Circulating levels of Ia antigen bearing T-lymphocytes from different lymphoid compartments of acutely diabetic and normoglycemic (but diabetes prone) BB rats were determined with monoclonal antibodies in an effort to analyze the temporal relationship between levels of this unusual T cell antigen and the onset of diabetes. In young normoglycemic rats elevated blood levels of Ia-positive T-lymphocytes (greater than or equal to 4.00%) predicted the future development of hyperglycemia with a sensitivity of 85% and a specificity of 83%. The interval between the identification of these elevated levels and the onset of diabetes ranged from 22 to 82 days. After the development of hyperglycemia the level of Ia-positive T-lymphocytes declined progressively in all lymphoid compartments with chronicity of the diabetes. We conclude that Ia antigens bearing T cells serve as immunologic "markers" of susceptibility to diabetes in this "high-risk" population and probably reflect an ongoing immune process during the prediabetic state. Similar findings in humans with a family history of diabetes might lead to identification of prediabetic individuals and allow selective use of immunomodulation to prevent the disease.

Acute Disease↗
PubMed1985

Increased incidence of Ia antigen-bearing T lymphocytes in the spontaneously diabetic BB rat.

The frequency of Ia-positive T lymphocytes in spontaneously diabetic BB rats was assessed by using monoclonal antibodies and a fluorescence-activated cell sorter. These cells peaked in frequency during the early stages of hyperglycemia, with a gradual decline toward normal as the disease progressed. Significantly increased numbers of Ia-positive T cells were detected in both helper (W3/25+) and cytotoxic-suppressor (OX8+) subsets. The elevated levels of Ia-positive T lymphocytes in these rats may be relevant to the immune destruction of their beta cells.

Acute Disease↗
PubMed1984

Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants.

91 renal transplant candidates were randomised to receive Towne strain cytomegalovirus (CMV) vaccine or placebo at least 8 weeks before transplantation. The vaccine was well tolerated and there was no vaccine virus excretion. Serological and cellular immune responses developed in most vaccines but were lower in the transplant patients than in healthy volunteers and some of the seronegative patients failed to mount responses. CMV infection occurred in most of the seronegative vaccine-treated or placebo-treated patients who received kidneys from seropositive donors, but the illnesses were less severe in the vaccines than those in similarly exposed placebo-treated patients. Vaccine-treated patients who received kidneys from seronegative donors did not excrete virus, and therefore the vaccine virus was not reactivated from a putative latent state despite immunosuppression at the time of transplantation.

Antibodies, Viral↗
PubMed1984

Variable response to donor-specific blood transfusion in the rat.

In an attempt to study the generality of effect of donor-specific blood transfusions (DSBT) in inducing immunologic unresponsiveness, the survival rates of heart, pancreas, and skin allografts were compared in blood-pretreated animals. DSBT, when given in a single-dose or multiple-dose protocol, prolonged cardiac allograft survivals in some strain combinations (F----L, LBN----L), but not in others (BN----L, ACI----L, ACI----WF). Antilymphocyte serum further prolonged survivals in protocols in which blood pretreatment was effective, and proved capable of reversing a state of sensitization in rats treated with multiple small-volume transfusions. In no case did the protection afforded the cardiac allografts extend to pancreatic or skin allografts, even with the use of nonspecific immunosuppression and a weak histocompatibility barrier. Third-party cardiac allografts were not protected by the blood pretreatment, attesting to the specificity of the transfusion effect. Addition of azathioprine during the blood pretreatment neither interfered with nor significantly improved the results seen with transfusion alone. The graft prolongation that follows blood pretreatment appears to be influenced by many factors, such as donor-host histocompatibility, the specific tissue transplanted, the blood transfusion schedule, and the use of adjunctive immunosuppression--but presently it is an unpredictable phenomenon.

Animals↗
PubMed1984

The importance of immunologic factors in the pathogenesis of encephalomyocarditis virus induced diabetes in mice.

The pathogenesis of EMC virus induced diabetes has generally been thought to be caused by direct cytopathic effect of the virus on beta cells with susceptibility or resistance dictated primarily by the density of viral receptors on the beta cells of different individuals. The histological finding of insulitis, our demonstration of a protective effect of immunosuppression with ALS or anti-theta antibody and silica supports host immune factors as important determinants of susceptibility. A critical role of the immune system might be mediated by autoimmune destruction of EMC-virus infected beta cells. In susceptible strain mice treated with low dose cyclophosphamide to deplete suppressor cells, which may halt the autoimmune process and allow recovery, a prolonged period of hyperglycemia was demonstrated as compared to controls. Bone marrow exchanged between susceptible and resistant strains was also found to alter susceptibility. "B mice", deficient in T lymphocytes, when infected with EMC virus had a decreased incidence of diabetes. Susceptibility to EMC diabetes may be dictated by the autoaggressive response of host immune system to beta cells altered by EMC virus infection.

Animals↗
PubMed1984

Major histocompatibility complex restriction and transplantation immunity. A possible solution to the allograft problem.

Studies of the survival of weakly histoincompatible skin grafts in which the Langerhans' cells (LC)5 have been replaced with major histocompatibility complex (MHC)-compatible or incompatible LC, as well as studies of the fate of cultured endocrine allografts in MHC-compatible and incompatible mice and rats, indicate that allografts are only recognized as foreign if they possess donor macrophages (or cells of this family), or if antigen presenting cells MHC-compatible with the graft can be provided by the host.

Animals↗
PubMed1983

Mycobacterial infections in renal allograft recipients.

Primary mycobacterial infections developed in five of 565 patients who had transplants during a 15-year period. All had negative PPDs and normal chest roentgenograms; none had tuberculosis before transplantation. Atypical mycobacteria were cultured in three of five infections. All were treated with a multiple-drug regimen, including isoniazid, rifampin, ethambutol, and streptomycin sulfate. In four of five patients, there were serious drug-related complications. No major initial alteration of immunosuppressive therapy was necessary in any of the patients. During the study, a treatment policy was followed that included one year of isoniazid treatment of all recipients with a positive PPD, history of tuberculosis, chest x-ray film suggestive of tuberculosis, or PPD-positive donor. An additional 14 transplant recipients were treated in accordance with this policy without complications or subsequent mycobacterial infections (32-month average follow-up). Despite the low incidence of mycobacterial infection in this series, the potential lethality and morbidity mandate constant vigilance.

Adult↗