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Carla Greenbaum

Publications and source records attributed to Carla Greenbaum.

10 recordsLinked to original sources
PubMed2006

Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects.

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is recognized as a major autoantigen for autoimmune type 1 diabetes (T1D) in the NOD mouse model. This study was undertaken to examine CD4+ T cell responses toward IGRP in human subjects. The tetramer-guided epitope mapping approach was used to identify IGRP-specific CD4+ T cell epitopes. IGRP(23-35) and IGRP(247-259) were identified as DRA1*0101/DRB1*0401-restricted epitopes. IGRP(13-25) and IGRP(226-238) were identified as DRA1*0101/DRB1*0301-restricted epitopes. IGRP-specific tetramers were used to evaluate the prevalence of IGRP-reactive T cells in healthy and T1D subjects. More than 80% of subjects with either DRB1*0401 or DRB1*0301 haplotype have IGRP-specific CD4+ T cell responses for at least one IGRP epitope. IGRP-specific T cells from both healthy and T1D groups produce both gamma-IFN and IL-10. DRA1*0101/DRB1*0401 IGRP(247-259)-restricted T cells also show cross-reactivity to an epitope derived from liver/kidney glucose-6-phosphatase. The detection of IGRP-reactive T cells in both type 1 diabetic subjects and healthy subjects and recent reports of other autoreactive T cells detected in healthy subjects underscore the prevalence of potentially autoreactive T cells in the peripheral immune system of the general population.

Adult↗
PubMed2006

Specific human leukocyte antigen DQ influence on expression of antiislet autoantibodies and progression to type 1 diabetes.

CONTEXT: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk. OBJECTIVE: The objective of the study was to analyze whether HLA DQ alleles influence the development of antiislet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both. DESIGN: The Diabetes Prevention Trial-1 screened more than 90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody (ICA) expression between 1994 and 2002. SETTING: The study was conducted in the general community. PARTICIPANTS: The Diabetes Prevention Trial-1 found 2817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65, ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for progression to diabetes for up to 8 yr (median, 3.6 yr). MAIN OUTCOME MEASURE: Progression to T1DM was measured. RESULTS: High-risk DQ haplotypes and genotypes were associated with a higher percentage of relatives expressing multiple biochemical autoantibodies and higher T1DM risk (e.g., respectively, 59 and 36% at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype). The number of autoantibodies expressed significantly increased T1DM risk and across different DQ genotypes, autoantibody positivity directly correlated with diabetes risk. However, multivariate analyses indicated that the influence of most genotypes on T1DM risk was not independent from autoantibody expression, with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic combinations conferred 5-yr diabetes risks significantly lower (e.g. 7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201 and 14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were found in other combinations. CONCLUSION: HLA DQ alleles determine autoantibody expression, which is correlated with diabetes progression. Among autoantibody-positive relatives, most HLA DQ genotypes did not further influence T1DM risk.

Adolescent↗
PubMed2005

Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects.

Glutamic acid decarboxylase 65 (GAD65) is a putative autoantigen associated with the pathogenesis of type 1 diabetes (T1D). The prevalence of autoreactive CD4+ T cells towards the immunodominant GAD65(555-567) epitope in DR4 healthy and T1D subjects was investigated with class II tetramers. A slightly higher percentage of diabetic subjects had GAD65(555-567) tetramer-positive T cells upon GAD65(555-567) peptide stimulation on the total CD4+ T-cell populations compared to healthy subjects. In contrast, three quarters of subjects in both groups had tetramer-positive T cells resulting from stimulation of the CD4+CD25+ regulatory T-cell depleted CD4+ T cells. The frequencies and TCR Vbeta gene usages of GAD65(555-567) T cells were also similar in both groups. Experiments demonstrated that GAD65(555-567)-reactive T cells in healthy and diabetic subjects had different CD45RA phenotypes. For the healthy group, GAD65(555-567)-reactive T cells were generally found in the CD45RA+ naïve T-cell pool while GAD65(555-567)-reactive T cells from T1D subjects were present in both CD45RA+ naïve and CD45RA- memory T-cell pools. These findings suggested that there is no difference in thymic selection of DR4 restricted GAD-reactive T cells amongst healthy and T1D individuals but GAD65(555-567)-reactive T cells have been preferentially activated in diabetic patients.

CD4-Positive T-Lymphocytes↗
PubMed2005

Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1.

OBJECTIVE: This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes. RESEARCH DESIGN AND METHODS: We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26-50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes. RESULTS: Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) > or =80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). CONCLUSIONS: It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.

Administration, Oral↗
PubMed2004

Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus--a new surrogate measure of non-progression?

Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high-risk non-diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non-progressors, as opposed to progressors, there was no fall in C-peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C-peptide production in the prediabetic period appears to indicate non-progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.

Adolescent↗
PubMed2004

GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes.

Negative selection of self-reactive T-cells during thymic development, along with activation-induced cell death in peripheral lymphocytes, is designed to limit the expansion and persistence of autoreactive T-cells. Autoreactive T-cells are nevertheless present, both in patients with type 1 diabetes and in at-risk subjects. By using MHC class II tetramers to probe the T-cell receptor (TcR) specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes, we identified high-avidity CD4+ T-cells in peripheral blood, coexisting with low-avidity cells directed to the same GAD65 epitope specificity. A variety of cytokine patterns was observed, even among T-cells with high MHC-peptide avidity, and the clones utilize a biased set of TcR genes that favor two combinations, Valpha12-beta5.1 and Valpha17-Vbeta4. Presence of these high-avidity TcRs indicates a failure to delete autoreactive T-cells that likely arise from oligoclonal expansion in response to autoantigen exposure during the progression of type 1 diabetes.

Antibody Affinity↗
PubMed2004

Male sex increases the risk of autoimmunity but not type 1 diabetes.

OBJECTIVE: The goal of this study was to explore the role of sex on the prevalence of autoantibodies, protective genetic subtypes, beta-cell function, and the incidence of type 1 diabetes in a population of first- and second-degree relatives of patients with type 1 diabetes (probands). We examined both the effect of the sex of the individual screened as well as the effect of the sex of the individual's proband on diabetes risk variables tested. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Trial-Type 1 has screened 93,188 relatives of type 1 diabetic patients from February 1994 to January 2002. After observing that more men than women were islet cell autoantibody (ICA) positive for the group as a whole, we further explored the role of sex by detailed analysis of variables in this population. RESULTS: Our data suggest only an influence of sex on the type 1 diabetes disease process. After adjustment for race, age, and relationship to proband, male sex was associated with the appearance of autoimmunity, i.e., the presence of ICA and having two or more antibodies. There was no effect of sex on the presence of other autoantibodies, insulin secretion, results of oral glucose tolerance test, or development of diabetes. CONCLUSIONS: Our finding that male sex conveys an independent increased risk for development of ICA and multiple antibodies, while at the same time finding no difference with respect to the development of diabetes, suggests that male relatives with the known risk factor of ICA are less likely than comparable female relatives to progress to overt disease, that the pathogenesis of type 1 diabetes among men is slower compared with women, or that women develop diabetes manifesting different antibody responses.

Adolescent↗
PubMed2002

The antibody response to bacteriophage is linked to the lymphopenia gene in congenic BioBreeding rats.

Congenic BioBreeding (BB) rats, homozygous for the autosomal lymphopenia (Lyp) gene (Lyp/Lyp), heterozygous (Lyp/+), or wild-type (+/+), were immunized with the T cell-dependent bacteriophage PhiX174 to determine effects of Lyp on primary and secondary antibody responses. The primary PhiX174 antibody response did not differ between the three different genotypes. In contrast, the secondary immune response, expressed as the peak neutralizing titer, was markedly reduced in Lyp/Lyp (9.9+/-3.2; mean value+/-S.E.M. for seven rats) compared to both Lyp/+ (51+/-12; n=13; P=0.006) and +/+ (100+/-20; n=7; P=0.004) BB rats. We suggest that the secondary antibody response to the T cell-dependent neoantigen PhiX174 is linked in a recessive manner to genetic factor(s) in the Lyp gene region.

Animals↗