Immunogenicity of recombinant DNA human insulin

Fineberg, S. Edwin; Galloway, John A.; Fineberg, Naomi S.; Rathbun, M. J.; Hufferd, S.

doi:10.1007/bf00284452

Cited by 155 publications

(75 citation statements)

References 21 publications

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“…Similar studies carried out on individuals treated only with human insulin would help contrast the response with heterologous insulin and establish the role of both processed antigenic determinants and zinc-induced changes in immunogenicity. The detection of anti-insulin antibodies in subjects treated only with human insulin (13,14) suggests that helper T cells recognizing human insulin can develop without the use of animal insulins.…”

Section: Resultsmentioning

confidence: 99%

“…In those studies, the critical epitopes on the insulin molecule recognized by T lymphocytes were surmised from amino acid differences between autologous insulin and immunizing insulins. Several recent studies, however, indicate that anti-insulin antibody can be detected in subjects treated only with human insulin preparations (13,14) and in type I diabetics prior to insulin therapy (15,16). In addition, recent studies in mice have shown that both helper and suppressor T cells are primed by insulins presumed to be "nonimmunogenic" (17,18) and suggest that recognition of amino acid exchanges is not the only factor determining insulin immunity.…”

Section: Introductionmentioning

confidence: 99%

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Recognition of human insulin in vitro by T cells from subjects treated with animal insulins.

Nell¹,

Virta²,

Thomas³

1985

J. Clin. Invest.

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Structurally defined proteins and peptides have provided considerable information about the specificity and regulation of immune responses in inbred animals. Many diabetics require therapy with insulin; therefore, we used this defined protein as a model antigen to investigate immune responses in the outbred human population. In this report, we examine human T cell recognition of antigenic determinants on various insulins. A group of 25 subjects was selected from over 200 diabetics because of the magnitude of their in vitro responses. 13 of the 25 had significant T cell responses to human insulin despite treatment with only beef/pork insulin mixtures. This autoimmunity may be attributed to crossreactivity of lymphocytes highly reactive to "foreign" epitopes on therapeutic insulins. Alternatively, identical determinants shared by human and animal insulins may be recognized. By employing additional insulins not used therapeutically and isolated A and B chains, several potential mechanisms for lymphocyte autoreactivity to human insulin were demonstrated. Some epitopes are conformational and require recognition of an intact molecule, whereas other epitopes may arise from antigen processing at the cellular level. Studies using zinc-free insulins suggest that zinc-induced alterations of the molecular surface may result in some shared reactivities between animal and human insulin. Furthermore, T cell reactivity against "foreign" epitopes is more complex than anticipated from differences in amino acid sequence. The response patterns of many subjects indicate that the A-chain loop associates with the N-terminal B chain to form a complex determinant. This determinant is recognized more often than individual amino acids. We conclude that insulin therapy generates polyclonal T cell responses directed at multiple epitopes on the molecule. Many of these epitopes are not identified by amino acid exchanges and their presence on human insulin leads to apparent autoimmunity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recognition of human insulin in vitro by T cells from subjects treated with animal insulins.

Nell¹,

Virta²,

Thomas³

1985

J. Clin. Invest.

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“…Insulin antisera was obtained from Linco Research Inc. (Eureka, Mo, USA). To avoid inclusion of amniotic fluid insulin data in which the presence of high endogenous insulin antibody levels could influence the insulin assay results, amniotic fluid insulin antibody concentration was measured [16]. C-peptide determinations were made using commercially available RIA reagents (Serono Diagnostics, Boston, Mass., USA) or tyrosylated 125I-Cpeptide (Eli Lilly) and guinea pig C-peptide antisera (Linco).…”

Section: Laboratory" Measurementsmentioning

confidence: 99%

Direct relationship of antepartum glucose control and fetal erythropoietin in human Type 1 (insulin-dependent) diabetic pregnancy

et al. 1990

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Summary. In the present study the antepartum relationship between maternal diabetic glucose control and fetal hypoxaemia was examined in 44 Type i (insulin-dependent) diabetic and 23 non-diabetic control pregnancies. Maternal HbAlc was used to assess maternal integrated blood glucose control while fetal metabolic control was evaluated by antepartum glucose, insulin, and C-peptide determinations in amniotic fluid at elective caesarean delivery. Fetal hypoxaemia was assessed indirectly by fetal umbilical vein plasma erythropoietin level at delivery. A prospectively developed statistical pathway model was used to examine the relationship of these variables. In applying forced stepwise multiple regression with this model, we observed in the diabetic subjects that mean maternal HbA~c during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery (r = 0.57,p < 0.001). Additional significant contributions to umbilical venous erythropoietin were found for amniotic fluid glucose and amniotic fluid insulin when these two independent variables were added in stepwise fashion (p < 0.01). We conclude that in diabetic pregnancy, antepartum control of maternal hyperglycaemia is a significant factor associated with fetal hypoxaemia. We speculate that this effect is mediated through perturbations which accelerate fetal metabolism and which is expressed by amniotic fluid levels of glucose and insulin.Key words: Erythropoietin, HbAlc, fetus, oxygenation, diabetes mellitus.Although in recent years the outcome of diabetic pregnancies has dramatically improved, fetal and neonatal morbidity and mortality remain increased relative to normal pregnancies [1,2]. Some of the pathological features observed in offspring of these pregnancies have been shown to be associated with maternal hyperglycaemia (eg., respiratory distress syndrome, congenital malformations, and neonatal hypoglycaemia); others have not. Among the latter are the increased incidence of late gestation fetal death, antepartum and intrapartum fetal distress, and neonatal polycythaemia. We and others have speculated that these features of diabetic pregnancies have their origins in chronic and/or acute fetal hypoxaemia [3][4][5].The purpose of the present study was to indirectly examine the antepartum relationship between chronic maternal hyperglycaemia and fetal oxygenation in Type 1 (insulin-dependent) diabetic pregnancies delivered by elective caesarean section before the confounding effect of labour [6]. To do so, we prospectively developed a hypothetical pathway model for statistical analyses in which chronic maternal hyperglycaemia was related to chronic fetal hypoxaemia through several intermediate steps. Subjects and methods SubjectsAfter obtaining approval by the Ethical Committee at the University of Helsinki and after obtaining each patient's consent, control and Type i (insulin-dependent) diabetic subjects carrying singleton fetuses were studied at the Women's Hospital of the University Central Hospital of Helsink...

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“…Although mean antibody levels are now lower in patients treated with subcutaneous human insulin, ϳ50% of such patients have measurable IABs (2). Since the initial description of IABs in the 1950s, the effect of antibody development, from low levels at baseline to levels commonly observed during clinical therapy, on key glycemic parameters has not been tested in a prospectively designed randomized controlled study.…”

mentioning

confidence: 99%

The Effect of Insulin Antibodies on the Metabolic Action of Inhaled and Subcutaneous Insulin

et al. 2005

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OBJECTIVE -To assess the impact of the development of high-or low-affinity insulin antibodies (IABs) on postprandial glucose tolerance, duration of insulin action, and clinical safety in patients with type 1 diabetes receiving inhaled insulin (Exubera). RESEARCH DESIGN AND METHODS-This study consisted of a prospective, randomized, open-label, parallel-group trial in which 47 patients with type 1 diabetes received NPH insulin twice daily plus either premeal inhaled insulin (INH group; n ϭ 24) or premeal subcutaneous regular insulin (SC group; n ϭ 23) for 24 weeks. Meal challenge and euglycemic clamp studies were performed on consecutive days at baseline, week 12, and week 24. Adverse events were monitored.RESULTS -For the INH and SC groups, mean (ϮSD) IAB levels were 3.5 Ϯ 3.9 and 2.6 Ϯ 4.1 U/ml at baseline, respectively, compared with 101.4 Ϯ 140.4 and 4.3 Ϯ 9.4 U/ml at week 24. At week 24, the changes from baseline were similar for the INH and SC groups for maximal plasma glucose concentration (C max ) (adjusted ratio for treatment group difference 0. B efore the introduction of highly purified porcine and recombinant human insulins into clinical practice, the use of less purified animal-derived insulin in patients with diabetes was associated with a near 100% prevalence of detectable insulin antibodies (IABs) (1). Although mean antibody levels are now lower in patients treated with subcutaneous human insulin, ϳ50% of such patients have measurable IABs (2). Since the initial description of IABs in the 1950s, the effect of antibody development, from low levels at baseline to levels commonly observed during clinical therapy, on key glycemic parameters has not been tested in a prospectively designed randomized controlled study.Multiple cross-sectional studies over the years have investigated whether IABs can cause alterations in insulin pharmacokinetics or pharmacodynamics. Although some studies have shown associations between IABs and delayed rises in free insulin concentrations (3,4) or prolonged half-life of free insulin (3,5) after insulin dosing, the clinical impact of these observations remains unclear (6). Using a standardized meal challenge test, one study showed a relationship between high-affinity IAB binding and impaired postprandial glucose tolerance (7), although such a relationship has not been consistently reported (8,9). Significantly, although some studies have reported a deleterious effect of IABs on long-term glycemic control (10 -12), most have not (8,(13)(14)(15)(16)(17)(18). Notably, the syndrome of immunologic insulin resistance has been reported in patients with high levels of maximum insulin binding (5).Furthermore, reports of prolongation of insulin half-life have not been associated with an increased incidence of clinical hypoglycemia (14), although rare cases of unusual hypoglycemic syndromes associated with insulin therapyrelated antibodies have been described (19 -21). In addition, hypoglycemia thought to be due primarily to high levels of low-affinity binding has been described in th...

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Immunogenicity of recombinant DNA human insulin

Cited by 155 publications

References 21 publications

Recognition of human insulin in vitro by T cells from subjects treated with animal insulins.

Recognition of human insulin in vitro by T cells from subjects treated with animal insulins.

Direct relationship of antepartum glucose control and fetal erythropoietin in human Type 1 (insulin-dependent) diabetic pregnancy

The Effect of Insulin Antibodies on the Metabolic Action of Inhaled and Subcutaneous Insulin

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