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Biomedical subjects

J H Helderman

Publications and source records attributed to J H Helderman.

At least 91 records · Page 5Linked to original sources
PubMed1984

Effect of insulin and transferrin in the maintenance of the activated state of the T-lymphocyte induced by allo-antigen.

Insulin is an immuno-modulating molecule enhancing cytotoxic T-cell function and supporting intermediary metabolism in activated lymphocytes. Insulin also maintains the activated state of mitogen-stimulated lymphocytes. Because of the importance of allo-antigen response of diabetic patients for infections and transplant immunity, we explored the role of insulin in the allo-activated state of lymphocytes. Allo-stimulation was provided in one-way mixed lymphocyte reactions, with Balb/C mouse lymph node cells responding to irradiated spleen cells of C57BL/6 mice, in culture under conditions which permitted evaluation of hormonal modulation. Mixed lymphocyte reactions established in fetal calf serum, insulin-depleted by passage over antibody affinity columns, were of equal magnitude to those in insulin-replete serum. A weak but positive mixed lymphocyte reaction can be effected with an artificial serum substitute containing no additional hormone. Provision of insulin (10 nmol/l) restored a full mixed lymphocyte reaction response which was mimicked by addition of transferrin. The insulin-transferrin combination was not additive. In conclusion, insulin and transferrin maintain the allo-activated state of the mouse lymphocyte, transferrin alone being sufficient when full antigenic stimulation is provided. If the same applies to human lymphocytes, insulin-deficient diabetic patients will respond to full allo-antigen challenge, and so should be fully capable of mounting a transplant immune response.

Animals↗
PubMed1984

Progressive multifocal leukoencephalopathy in a renal transplant recipient. Increased diagnostic sensitivity of computed tomographic scanning by double-dose contrast with delayed films.

A progressive, deteriorating neurologic disorder developed in a 28-year-old white man 10 years after he successfully received a living related donor kidney transplant. An extensive neurologic evaluation was unrevealing, including normal results of computed tomographic scanning of the brain with and without contrast medium. Repeated computed tomographic scanning after a double dose of radiocontrast medium in conjunction with delayed imaging revealed multiple areas of abnormal enhancement. This technique helped to direct brain biopsy, which led to the early diagnosis of progressive multifocal leukoencephalopathy and the institution of specific therapy.

Adult↗
PubMed1984

Prospective evaluation of renal allograft dysfunction with 99mtechnetium-diethylenetriaminepentaacetic acid renal scans.

A prospective, single-blinded study was done to determine the ability of serial 99mtechnetium-diethylenetriaminepentaacetic acid scans to diagnose renal allograft rejection. Among 28 transplant recipients 111 renal scans were obtained 1 day postoperatively and every 3 to 4 days thereafter for 3 weeks in all patients retaining an allograft. Computer-generated time-activity blood flow curves were analyzed semiquantitatively for the 1) interval between curve peaks of the allograft and iliac artery, 2) renal transit time and 3) renal washout of radionuclide. Excretory function was assessed by degree and interval to appearance of radionuclide in the calices and bladder. Deterioration of renal blood flow and excretion compared to the initial scan was considered rejection. Of 52 scans performed during clinical rejection 47 (90.4 per cent) were interpreted as showing rejection (sensitivity). Of 53 scans interpreted as showing rejection 47 (88.7 per cent) were positive for clinical rejection. The remaining 6 patients (initial false positive results) suffered clinical rejection within 24 to 72 hours. We conclude that 99mtechnetium-diethylenetriaminepentaacetic acid renal scans are useful in the differential diagnosis of renal allograft dysfunction.

Clinical Trials as Topic↗
PubMed1984

Perturbation of epidermal Langerhans cells in immunosuppressed human renal allograft recipients.

As an initial attempt to gain a better understanding of the basis for the increased incidence of ultraviolet-light-related skin cancer in chronically immunosuppressed human renal allograft recipients, we have compared both morphological and functional characteristics of epidermal Langerhans cell (LC) populations present in the forearm skin of nine such patients with those of age, sex, and race-matched controls. The LC surface densities in vacuum-induced blister-derived epidermal sheets taken simultaneously from extensor and flexor forearm skin of the patients were significantly lower than those observed in the controls. The most abnormal LC densities seen were in the patients' extensor forearm skin. Likewise there were disturbances in LC distribution and morphology that were most marked in the extensor forearm skin of patients. Differences in the alloantigen-presenting capacity of LCs present in epidermal cell suspensions prepared from patient and control forearm skin were also noted--however, these differences were not as great as were the LC density differences. The alloantigen-presenting capacity of patients' LCs was depressed proportionately more than was the alloantigen presenting capacity of their peripheral blood mononuclear cells. These results demonstrate that the LC population is clearly perturbed in human renal allograft recipients and that this perturbation is greatest in a sun-exposed region of skin.

Adult↗
PubMed1984

Lymphocyte function in patients treated with monoclonal anti-T3 antibody for acute cadaveric renal allograft rejection.

We are participating in a multicenter trial testing the efficacy of a murine monoclonal antihuman peripheral T lymphocyte antibody (OKT3.PAN) as immunosuppressive therapy for the treatment of acute cadaveric renal allograft rejection. Although clinical data indicate that administration of this antibody clears the circulating lymphocyte pool of T3-positive cells, some in vitro studies have called into question whether the antibody is indeed lymphocytotoxic. Other in vitro data suggest that the antibody is a potent mitogen. To address these problems and investigate the effect of the antibody on T cell function, we have studied spontaneous blastogenesis, response to the lectins phytohemagglutinin (PHA) and concanavalin A (ConA), and response to donor-specific and non-donor-specific alloantigen in a one-way MLC in 9 patients treated with anti-T3 for acute rejection and 9 steroid-treated controls. Patients cells were harvested with standard techniques and studied after transplantation, but prior to acute rejection, on days 3 and 12 of therapy and 1 week after cessation of therapy. All patients received baseline immunosuppression with azathioprine and steroids. Acute rejection was reversed with alpha T3 antibody (5 mg i.v./day-1 X 14 days) in 8 of 9 patients and in 6 of 9 steroid-treated controls. Spontaneous blastogenesis was not enhanced by anti-T3 nor did it rise during therapy. PHA and Con A responsiveness were dramatically and significantly depressed by therapy with anti-T3 or steroids on days 3 and 12. Although PHA responsiveness rebounded past baseline 1 week after monoclonal therapy, it was depressed compared with the steroid-treated patients. On the other hand, Con A responsiveness was still significantly depressed one week after monoclonal therapy compared with prerejection values or with controls. Response to donor-specific and to non-donor-specific alloantigen was significantly depressed with anti-T3 therapy compared with steroid controls, and it did not rise during therapy. Donor-specific responses tended to be slower in returning to pretreatment values in the OKT3 patients compared with steroid controls. In summary: (1) Anti-T3 antibody did not enhance spontaneous blastogenesis in patients treated for acute rejection; (2) Con A and PHA responses were dramatically depressed by anti-T3 therapy and returned to baseline following different time courses; (3) Non-donor-specific alloresponse and, more important, donor-specific alloresponse, was more depressed--and for longer periods--by anti-T3 than by conventional steroid anti-rejection therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1984

Acute regulation of human lymphocyte insulin receptors. Analysis by the glucose clamp.

The T lymphocyte insulin receptor model has been used to explore the regulation of insulin receptor appearance in that lymphocytes do not bear the insulin receptor in the circulation and thus are not amenable to regulation by virtue of ligand binding. Such cells synthesize insulin receptors when stimulated by antigen in vivo or in vitro. In these studies, the glucose clamp technique was employed to isolate perturbations in plasma glucose and plasma insulin as potential mediators of the regulation of the mitogen-induced T lymphocyte insulin receptor. Nondiabetic, normal weight individuals volunteered for 10 hyperglycemic clamp studies and nine euglycemic clamp studies with five individuals studied by both protocols. Hyperglycemia and hyperinsulinemia were created by the hyperglycemic clamp (basal plasma glucose was increased from 89 +/- 2 mg/dl to 230 +/- 2 mg/dl and an insulin of 99 +/- 8 microU/ml was reached). Blood was removed for isolation of T lymphocytes at 0, 1, 3, and 4 h of the clamped condition. After 1 h of hyperglycemia accompanied by an elevated plasma insulin, T cell insulin binding fell from 9.9 +/- 0.9 pg/10(6) lymphocytes to 8.5 +/- 0.9 pg/10(6), and reached a nadir of 19 +/- 4% at the conclusion of the clamp. Scatchard analysis of binding data from two of the subjects who underwent the hyperglycemic clamp demonstrated a reduction of the number of binding sites per cell without a change in the affinity of ligand for receptor. To separate the effects of glucose and insulin and the manner in which insulin is provided, the 4-h euglycemic clamp was performed in which fasting plasma glucose was maintained (95 +/- 2 mg/dl) while constant hyperinsulinemia was created (80 +/- 3 microU/ml). Insulin binding to activated, cultured T lymphocytes demonstrated a similar fall in insulin binding. Scatchard analysis of three additional studies again revealed a reduction in receptor number to approximately 40% of base line. These studies reveal that T cell insulin receptor regulation is achieved by hyperinsulinemia independent of the glucose level achieved. The reduction in insulin binding and receptor number could not be accounted for by variations in the strength of lectin stimulation, the time course of lectin response, or by the stress of the clamp itself. The effect of the clamp was specific for the lymphocyte insulin receptor in that the clamp had little effect on the interleukin II receptor activation marker. Acute changes in plasma insulin by the glucose clamp technique are perceived by the T lymphocyte and displayed in tissue culture by an alteration in lectin-induced insulin receptors. One can conclude that rapid changes in ambient in vivo insulin concentrations can regulate the synthesis of T lymphocyte insulin receptors generated in vitro.

Adult↗
PubMed1983

Renal transplantation in diabetic patients: the end result does justify the means.

There were 49 insulin-dependent diabetics who received 52 renal allografts: 13 from living related and 39 from cadaveric donors. The mean age and time on dialysis were similar for both recipient groups. Patient survival at 1 and 2 years was 100 per cent for living related donor recipients, and 76 and 56 per cent at 1 and 2 years for cadaveric recipients. Renal allograft survival was 92 and 85 per cent at 1 and 2 years for living related donor recipients. Cadaveric allograft survival was 49 and 41 per cent at 1 and 2 years. The cumulative mortality rate was 39 per cent and the over-all surgical morbidity was low. Renal transplantation in diabetic patients is worthwhile from the standpoint of patient and allograft survival.

Adult↗
PubMed1983

Urologic complications in 505 renal transplants with early catheter removal.

Of 505 consecutive renal transplants urologic complications occurred in 4.1 per cent of cadaver, 2.6 per cent of living related, 1.9 per cent of diabetic and 3.8 per cent of nondiabetic allografts. Over-all, patient survival and graft salvage rates were 94 and 83 per cent, respectively. Principles of prevention, diagnosis and management of these complications are discussed. In contrast to prior standards the bladder catheter was removed within 36 hours postoperatively in nearly all cases without any increase in morbidity.

Graft Survival↗
PubMed1983

Transplantation 1983.

Renal transplantation has entered a new era of optimism characterized by steady increases in our scientific appreciation of the transplant event and improving allograft survival rates. Advances in tissue typing, methods of preventing rejection including an appreciation of the blood transfusion effect and the discovery of new immunosuppressive drugs such as cyclosporin A, and methods of rejection treatment have been responsible for this new era. With renewed impetus, continued advances can only increase an optimistic approach to renal transplantation.

Antibodies, Monoclonal↗
PubMed1983

Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium.

The effect of thiazide diuretics on the glucose tolerance of seven normal men in whom potassium loss was prevented with supplementation was studied using the glucose clamp technique. An initial control 2-h hyperglycemic clamp was performed to create a square wave of hyperglycemia 125 mg/dl above basal. At 1 h, 40 g glucose/m2 body surface area was ingested. Serial insulin (IRI) and gastric inhibitory polypeptide (GIP) levels were measured as well as the level of glucose infusion necessary to maintain the stable hyperglycemic level. After the initial study, subjects were placed on a 10-day course of 100 mg hydrochlorothiazide and 80 meq potassium per day. Subjects were monitored for dietary potassium intake, urinary potassium, and sodium losses, and the replacement of potassium adjusted accordingly. A repeat glucose clamp was done on day 10. When potassium losses were prevented, thiazides induced no alterations in glucose tolerance, beta-cell sensitivity to glucose, GIP-cell sensitivity to glucose, beta-cell sensitivity to GIP, or tissue sensitivity to insulin. Two control studies in which hypokalemia was allowed to ensue after hydrochlorothiazide ingestion revealed a diminution in glucose tolerance, a consequence of diminished pancreatic beta-cell response to glucose. We conclude that the thiazide effect on glucose tolerance is a consequence of the resultant hypokalemia that the diuretic may create.

Adolescent↗
PubMed1983

Disease due to cytomegalovirus and its long-term consequences in renal transplant recipients. Correlation of allograft survival with disease due to cytomegalovirus and rubella antibody level.

We prospectively studied 52 consecutive renal allograft recipients who retained their grafts at least three months. The transplant recipients were observed for five years or longer. Disease due to cytomegalovirus (CMV) occurred in nine (17.3%). Manifestations of disease due to CMV that were significantly more common than in chronologically matched controls in comparable periods after transplantation included fever, leukopenia, hepatic function abnormalities, pneumonia, and renal dysfunction. Life-table analyses suggested a trend of decreased allograft survival with disease due to CMV, but the difference between controls was not statistically significant. A significant inverse correlation were noted between the level of hemagglutination inhibition antibody to rubella virus reached after transplantation and allograft survival. This correlation remained statistically significant even when patients with disease due to CMV were excluded from the analysis.

Actuarial Analysis↗
PubMed1981

Rapid mixed lymphocyte culture testing by analysis of the insulin receptor on alloactivated T lymphocytes: implications for human tissue typing.

Responses in the mixed lymphocyte culture (MLC) are traditionally evaluated by measurement of DNA synthesis or blast transformation. However, these events occur too late in the MLC to permit prospective matching for cadaveric renal transplantation. Presentation of allogeneic cells to the T lymphocyte within the MLC results in the emergence of an insulin receptor pharmacokinetically similar to that on other tissues such as fat, liver, and muscle. Intrafamilial MLC were studied by simultaneous assessment of DNA synthesis and insulin receptor binding. In 68 studies from seven families that provide examples of two haplotype identical matches, haplo-identical matches and total haplo mismatches, the presence of an insulin receptor correlated in every case with a positive MLC as estimated by [3H]thymidine incorporation. A quantitative relationship existed between the strength of the MLC and the amount of receptor binding. Based on analysis of cells from several families in which crossover events were known to have occurred, the appearance of an insulin receptor always corresponded with a mismatch at the portion of histocompatibility leukocyte antigen (HLA) chromosome bearing the D region. Finally, it was demonstrated in each of 30 cultures that insulin receptor emergence occurred significantly before detectable DNA synthesis, as early as 24 h after the initiation of the MLC, well within the time-constraint limitations for renal preservation. Appearance of the insulin receptor on activated lymphocytes may be a more rapid measure of mixed lymphocyte responses, and should permit prospective matching for cadaveric renal transplantation.

Cadaver↗
PubMed1981

Role of insulin in the intermediary metabolism of the activated thymic-derived lymphocyte.

The hypothesis that a role for insulin in the metabolism of T cells would be evident after cell activation when receptors appear was tested to validate the T cell model and to analyze the mechanism by which insulin may function in immunoregulation. Measuring the flux rates of 3-O-[methyl-3H]-D-glucose and aminoisobutyric acid, alpha-[1-14C], lactate production and oxidation, and glucose oxidation from carbon 1- and carbon 6-labeled substrates, it was determined that (a) mitogens such as phytohemagglutinin enhance basal T lymphocyte intermediary metabolism, (b) physiologic concentrations of insulin have no impact on the metabolism of unstimulated, cultured, receptor-negative lymphocytes, and (c) insulin provided to receptor bearing lymphocytes augments intermediary metabolism above mitogen stimulated levels. The importance of the pentose phosphate shunt pathway for energy metabolism in the stimulated lymphocyte was confirmed. These studies demonstrate that insulin has a classical physiologic role to play in the activated lymphocyte further validating the use of this cell to examine potential receptor defects in disorders of carbohydrate metabolism. By enhancing energy metabolism of stimulated lymphocytes, insulin serves biologic economy and thus may perform its immunoregulatory role.

3-O-Methylglucose↗