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Peter A Gottlieb

Publications and source records attributed to Peter A Gottlieb.

At least 19 recordsLinked to original sources
PubMed2006

CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.

Regulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4(+) T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3(+), including those that express low levels or no CD25. A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers. These cells were highly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25(+)CD4(+) and CD25(-)CD4(+) T cell subsets), were as suppressive as the "classic" CD4(+)CD25(hi) T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.

Adolescent↗
PubMed2005

Pharmacological characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist.

The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3-ylmethyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-acetamide (NBI-74330), from the T487 small molecule series. NBI-74330 demonstrated potent inhibition of [(125)I]CXCL10 and [(125)I]CXCL11 specific binding (K(i) of 1.5 and 3.2 nM, respectively) and of functional responses mediated by CXCR3, such as ligand-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, calcium mobilization, and cellular chemotaxis (IC(50) of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 >> CXCL10 > CXCL9. A comparison of the rank order of K(i) values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.

Acetamides↗
PubMed2005

CD4+CD25high regulatory T cells in human autoimmune diabetes.

In mouse models, CD4+CD25+ T cells are involved in maintenance of peripheral tolerance. In humans, a subset of CD4+CD25+ T cells expressing high levels of CD25 (CD4+CD25high) with characteristics identical to murine CD4+CD25+ was recently described. We evaluated the characteristics of CD4+CD25high T cells in peripheral blood of type 1 diabetic subjects (T1D) and normal controls (NC). In contrast to a previous report, we found no difference in the number of CD4+CD25high and CD4+CD25+ T cells between T1D and NC. We confirmed previous studies that demonstrated that human CD4+CD25high cells can suppress the proliferation of co-cultured CD4+CD25- cells stimulated in conditions of sub-maximal cross-linking by anti-CD3 either with or without anti-CD28. However, we did not observe statistical differences between the normal controls and the chronic diabetic subjects we tested. Culturing of these cell populations did not appear to affect their ability to suppress proliferation in both groups. In conclusion, we found no significant differences in number or in vitro regulatory function of CD4+CD25high in chronic human T1D subjects.

Adult↗
PubMed2005

Secondary attack rate of type 1 diabetes in Colorado families.

OBJECTIVE: Families of children diagnosed with type 1 diabetes require counseling concerning type 1 diabetes risk in nondiabetic siblings and parents. No U.S. population-specific life-table risk estimates are currently available for parents, and those for siblings (2-6% by age 20 years) are based on family studies completed before 1987. RESEARCH DESIGN AND METHODS: We analyzed family histories of 1,586 patients in Colorado with type 1 diabetes (83% non-Hispanic white, 10% Hispanic, and 7% other) diagnosed before 16 years of age and interviewed during 1999-2002. Families of probands with type 2, undetermined, or secondary diabetes (n = 53) or those with incomplete data (n = 137) were excluded. The median age at onset of the proband was 7.1 years and the median diabetes duration 3.5 years. Cumulative risk estimates were calculated using survival analysis for 2,081 full siblings and 3,016 biological parents. RESULTS: In siblings, the overall risk of type 1 diabetes by age 20 years was 4.4%, but it was significantly (P < 0.0001) higher in siblings of probands diagnosed under age 7 years than in those diagnosed later. In parents, the overall risk by age 40 years was 2.6% and higher in fathers (3.6%) than in mothers (1.7%) of probands (P < 0.001). Similar to siblings, the risk was also higher (P = 0.006) in parents of probands diagnosed <7 years of age than in those diagnosed later. CONCLUSIONS: Current risks of type 1 diabetes in Colorado siblings and parents of type 1 diabetic probands are higher than in the 1982 Pittsburgh study but similar to contemporary European rates. Recurrence risk of type 1 diabetes is significantly higher in first-degree relatives of probands diagnosed at a young age.

Adult↗
PubMed2005

Autoantibody "subspecificity" in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups.

OBJECTIVE: Autoimmune thyroid disease (AIT), celiac disease, and Addison's disease are characterized by the presence of autoantibodies: thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in AIT, tissue transglutaminase antibody (TTGAb) in celiac disease, and 21-hydroxylase antibody (21-OHAb) in Addison's disease. The objective of this study was to define the prevalence of these autoantibodies and clinical disease in a population with type 1 diabetes. RESEARCH DESIGN AND METHODS: We screened 814 individuals with type 1 diabetes for TPOAb, TGAb, TTGAb, and 21-OHAb. Clinical disease was defined by chart review. Factors related to the presence of autoimmunity and clinical disease including age at onset of type 1 diabetes, duration of diabetes, age at screening, sex, and the presence of autoantibodies were reviewed. RESULTS: The most common autoantibodies expressed were TPOAb and/or TGAb (29%), followed by TTGAb (10.1%) and 21-OHAb (1.6%). Specific HLA DR/DQ genotypes were associated with the highest risk for expression of 21-OHAb (DRB1*0404-DQ8, DR3-DQ2) and TTGAb (DR3-DQ2- DR3-DQ2). The expression of thyroid autoantibodies was related to 21-OHAb but not to TTGAb. The presence of autoantibodies was associated with and predictive of disease. CONCLUSIONS: In this large cohort of individuals with type 1 diabetes, the expression of organ-specific autoantibodies was very high. The grouping of autoantibody expression suggests common factors contributing to the clustering.

Adolescent↗
PubMed2004

Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high-risk population.

Individuals with type 1 diabetes mellitus (T1D) at risk for Addison's disease (AD) can be identified with RIAs for autoantibodies to the adrenal antigen 21-hydroxylase (21-OHAA). Screening individuals with T1D for 21OH-AA shows a relatively high prevalence of positive autoantibodies (1.4%, 38 of 2696 subjects). After detection of 21-OHAA, individuals were evaluated with endocrine testing, including baseline cortisol, ACTH, and plasma renin activity and low (1 mug) and high (250 mug) dose cortrosyn stimulation. Typing for DR and DQ alleles and for the major histocompatibility complex class I-related chain A (MICA) gene polymorphisms was performed. Six individuals were diagnosed with AD; five were identified on initial endocrine evaluation. Follow-up over 2.9 yr yielded one additional diagnosis of AD. Endocrine testing showed a correlation between baseline ACTH and peak cortisol (r = -0.61; P < 0.0001), baseline and peak cortisol (r = 0.70; P < 0.0001), and stimulated cortisol after low- and high-dose testing (r = 0.92; P < 0.0001). DR3-DQ2/DR4-DQ8 with DRB1* 0404 was associated with expression of 21-OHAA. At 2 yr, individuals homozygous for MICA5.1 had AD-free survival of 60% compared with 100% AD-free survival in those who were not homozygous for MICA5.1. Homozygosity for MICA5.1 may increase progression to overt AD among 21-OHAA-positive individuals.

Addison Disease↗
PubMed2004

HLA-DQ8-associated T cell responses to the diabetes autoantigen phogrin (IA-2 beta) in human prediabetes.

Susceptibility to type 1A autoimmune diabetes is linked to expression of particular MHC class II molecules, notably HLA-DQ8 in man and the orthologous I-Ag7 in the nonobese diabetic mouse. In the present study, we analyzed two peptide epitopes (peptides 2 and 7) from the diabetes autoantigen phogrin (IA-2beta), in the context of their presentation by the I-Ag7 and HLA-DQ8 molecules and their role as potential T cell antigenic epitopes in human diabetes. Both of these peptides are targets of diabetogenic CD4+ T cell clones in the nonobese diabetic mouse. Transgenic mice expressing HLA-DQ8 as the sole class II molecule generated a robust T cell-proliferative response when primed with peptide 2 or peptide 7 in CFA. Analysis of the IL-2 secretion from peptide 2-reactive T cell hybridomas stimulated with alanine-substituted peptides identified three residues that were crucial to the response. Among 41 islet cell Ag-positive prediabetic human subjects, 36.5% showed PBMC-proliferative responses to peptide 7, 17.1% to peptide 2, and 17.1% to both peptides; no response was seen among 20 matched healthy controls. Stratification of the data based upon HLA haplotype suggested that peptide 7 could be presented by at least one HLA-DR molecule in addition to HLA-DQ8, a finding that was supported by blocking studies with monomorphic mAbs. The results indicate that common phogrin peptides are targeted by autoreactive T cells in human and murine type 1A diabetes, and that the responses may in part be associated with the similar peptide-binding specificities of I-Ag7 and HLA-DQ8.

Adolescent↗
PubMed2004

Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine.

OBJECTIVE: To see if insulin glargine improves glycemic control in a clinical setting. RESEARCH DESIGN AND METHODS: A questionnaire and electronic database were used to assess glycemic parameters for 292 type 1 diabetic subjects taking > or =4 injections per day and receiving glargine as their only long-acting basal insulin for at least 6 months. Sixty-three subjects were taking glargine in the morning, 125 were taking glargine in the evening, and 104 were splitting the glargine dose between the morning and evening. RESULTS: The mean (+/-S.D.) age and duration of diabetes were 32 +/- 10 years and 15.9 +/- 10.3 years, respectively. The mean (+/-S.E.M.) durations of treatment with glargine were 13.1 +/- 0.6 months, 12.2 +.- 0.4 months, and 14.3 +/- 0.5 months for the morning, evening, and split treatment groups, respectively (P < 0.01). The A1C values improved significantly from baseline for the evening and the split dosage groups or when all groups were combined. The mean basal insulin dose was significantly reduced at the end of the study in all the three groups from baseline with no change in the short-acting insulin dose. The number of severe hypoglycemic episodes decreased from 379 in the year prior to glargine treatment to 167 in the post-glargine year. The weight gain was significantly higher in the group that took the split glargine dose (P < 0.01). CONCLUSIONS: Similar or improved glycemic control was achieved by administering glargine in the morning, evening, or using a split dose without any further increase in severe hypoglycemic episodes. Splitting the glargine dose did not offer any advantages in glycemic control parameters.

Adult↗
PubMed2004

Type 1 diabetes.

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Autoimmune Diseases↗
PubMed2004

T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading.

Human type 1 diabetes is thought to be mediated by autoreactive T cells specific for antigens expressed by pancreatic beta cells. However, it is unclear which autoantigens and determinants thereof are the targets of the autoimmune attack. Using comprehensive peptide libraries that cover the entire sequence of two major candidate autoantigens, GAD65 and proinsulin, we measured the in vivo frequencies of peptide-specific, IFN-gamma-producing memory T cells in 27 diabetic patients, 14 high risk individuals, and 15 partially HLA-matched healthy controls. Compared to the controls, both a higher number of determinants on the islet cell antigens were recognized and the frequencies of peptide specific cells were increased in patients and high risk individuals. Inclusion of signal enhancing anti-CD28 antibody further accentuated this difference. Considerable heterogeneity in peptide recognition was seen even in DRB1*04, DQB1*0302 matched individuals. Unlike its peptides, the GAD protein antigen did not recall a T cell memory response. The highly heterogeneous recognition of a multitude of peptide determinants on both autoantigens, occurring in the absence of protein recognition, and the low functional avidity of the memory cells involved jointly suggest that the autoimmune T cell repertoire in human type 1 diabetes primarily targets cryptic determinants engaged by determinant spreading.

Antigenic Variation↗
PubMed2004

Glycemic parameters with multiple daily injections using insulin glargine versus insulin pump.

This study compared external insulin pump treatment using insulin lispro or insulin aspart with multiple daily injections (MDI; four or more injections per day) using insulin glargine and insulin lispro or insulin aspart. An electronic database was used to retrieve various parameters of glycemic control for 515 adult patients with type 1 diabetes. An insulin pump was used by 216 patients, and 299 patients were taking insulin glargine for at least 6 months. The mean age (approximately 33 years), duration of diabetes (approximately 16 years), and duration of treatment (approximately 12 months) were similar for both the pump and insulin glargine groups. The mean (+/-SEM) A1C values were significantly reduced in both groups from the baseline to the end of the study (7.7 +/- 0.1% to 7.5 +/- 0.1% for the pump group and 8.0 +/- 0.1% to 7.7 +/- 0.1% for the insulin glargine group, P< 0.001) with similar weight gain (P> 0.05) in both groups. The insulin glargine group significantly reduced basal insulin intake at follow-up. The premeal boluses were similar throughout the study for both groups. The subjects reporting severe hypoglycemic episodes were similar in the two groups; however, there were 12 cases of diabetic ketoacidosis reported in the pump group and none in the insulin glargine group. Patients with type 1 diabetes can achieve similar glycemic control using insulin glargine with premeal insulin lispro or by using an external infusion pump with insulin lispro or insulin aspart. However, costs and episodes of diabetic ketoacidosis are significantly higher for insulin pump users.

Adult↗
PubMed2004

Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes.

BACKGROUND: The goal of new therapies introduced for type 1 diabetes should be to decrease hypoglycemic episodes while improving glycemic control. METHODS: A database was used to computer match the baseline A1C values in 196 subjects with type 1 diabetes receiving multiple daily injections (MDI) consisting of four or more injections per day. There were 98 patients transferred from NPH to insulin glargine (Lantus, Aventis Pharmaceuticals, Bridgewater, NJ), and 98 patients remained on NPH throughout the study. The gender distribution and mean age (approximately 32 years), duration of diabetes (approximately 16 years), and duration of treatment (approximately 13 months) were not significantly different between the groups. The majority of patients were well controlled (>50% in both groups had an A1C <7%). RESULTS: The mean A1c values were not significantly different in the groups at baseline or at follow-up. Severe hypoglycemic episodes per patient per year were significantly lower in the glargine group compared with the NPH group (0.5 vs. 1.2, respectively; P = 0.04). The mean end-of-study total (P = 0.03) and long-acting (P = 0.0001) doses were significantly reduced from baseline in the group that switched to glargine, but not in the group that remained on NPH, with no change in the short-acting dose in either group. The weight gain was significantly higher in the NPH group at the end of the study (P = 0.004) with no significant change in the glargine group. CONCLUSIONS: Transfer to glargine treatment from NPH in MDI regimens significantly reduces severe hypoglycemic episodes despite a decline in long-acting basal insulin without significant weight gain.

Adult↗
PubMed2002

Insulin-specific tolerance in diabetes.

At present it is possible to predict the development of type 1A diabetes (immune-mediated diabetes) in man and prevent the disorder in animals. Studies of immunity to insulin play a prominent role in both disease prediction and disease prevention. For both man and the NOD mouse, insulin autoantibodies usually precede the development of diabetes and can be utilized to assist in disease prediction. T cells clones recognizing insulin, both CD4 and CD8, can transfer disease to young mice or immunodeficient animals. Specific insulin peptides reacting with these clones have been identified, their crystal structure when bound to a human "diabetogenic" MHC allele has been determined, and specific peptides can be used either to induce or to prevent disease. Clinical trials of both insulin and an altered peptide ligand of insulin to prevent islet beta-cell destruction are underway. Insulin is one of a number of islet autoantigens, but it is likely that immune responses to insulin will be central to both pathogenesis and immunologic protection.

Animals↗
PubMed2002

The genetics of autoimmune polyendocrine syndrome type II.

A series of autoimmune disorders, often Addison's disease, type 1 diabetes mellitus, and thyroid autoimmunity, frequently occurs together in patients with the autoimmune polyendocrine syndrome type II (APS-II). The highest risk HLA genotype for Addison's disease, either as a single disease or in APS-II patients, consists of the genotype DR3/4, DQ2/DQ8 with DRB1*0404. As many as 30% of patients with Addison's disease have this genotype versus less than 0.5% of controls. An additional and important associated locus within the HLA region is the class I related gene, MIC-A. Patients who develop Addison's disease often have a delayed diagnosis and may die from Addisonian crisis; therefore, improved genetic testing combined with testing for 21-hydroxylase autoantibodies might allow the identification of relatively high-risk populations (greater than 1 in 200 defined genetic risk compared with 1 in 10,000 population risk).

Abatacept↗