Type 1 diabetes: recent developments.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
Edwin Liu
Publications and source records attributed to Edwin Liu.
Peptide-specific amelioration of T cell-mediated pathogenesis in murine type 1 diabetes.
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Animals↗
Celiac disease associated with type 1 diabetes mellitus.
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Autoantibodies↗
Preventing peptide-induced anaphylaxis: addition of C-terminal amino acids to produce a neutral isoelectric point.
BACKGROUND: Progress in peptide immunotherapy for the treatment of autoimmune diseases has been hampered by reports of anaphylactic reactions in both mice and human subjects. Fatal anaphylaxis in nonobese diabetic (NOD) mice has been described after repeated subcutaneous insulin peptide B:9-23 immunizations. On the basis of observations that rapid systemic delivery of peptide to a sensitized mouse (eg, intravenous delivery) increases the anaphylactic response, it was hypothesized that slowing down the absorption of the peptide would prevent anaphylaxis. OBJECTIVES: We sought to prevent anaphylaxis from B:9-23 peptide by altering the isoelectric point (pI) to neutral, thereby decreasing solubility and rate of absorption after subcutaneous injection. METHODS: B:9-23 peptide was modified by the addition of 2 arginine (RR) amino acids to the C-terminus to create B:9-23RR, thereby increasing the pI from 5.4 to 7.0. Both native and modified B:9-23 peptide were tested for the ability to induce anaphylaxis in a NOD mouse model of self-peptide anaphylaxis. RESULTS: This modification resulted in a peptide vaccine with decreased solubility when administered subcutaneously at a neutral pH. B:9-23RR significantly protected NOD mice from peptide-induced anaphylaxis compared with B:9-23 peptide. Furthermore, B:9-23RR peptide retains its ability to induce insulin autoantibodies and prevent diabetes in NOD mice. CONCLUSION: The modification of the pI of a peptide vaccine might be a generalizable method to prevent anaphylaxis without changing the immunologic properties.
Amino Acid Sequence↗
Genetic differentiation of poly I:C from B:9-23 peptide induced experimental autoimmune diabetes.
Type 1 diabetes is an immune-mediated disease, in which T cells of the adaptive immune system mediate beta cell destruction. Recently the innate immune system has been linked to etiopathogenesis of several autoimmune diseases including type 1 diabetes, as innate effector cells (e.g. dendritic cells, monocytes/macrophages and NK cells) can prime and promote or regulate (auto)immune responses. We have previously developed an experimental autoimmune diabetes (EAD) model with insulin peptide B:9-23 immunization in transgenic H-2(d)mice expressing the costimulatory molecule B7.1 in their islets (under the Rat Insulin Promotor, RIP). We compared the induction of diabetes with polyinosinic-polycytidylic acid (Poly I:C), a mimic of double stranded viral RNA versus insulin B:9-23 peptide in mice following backcrossing of the B7.1 transgene on to BALB/c mice from original B7.1 C57Bl/6 mice. We find that diabetes induction by Poly I:C is C57Bl/6 associated, whereas B:9-23 peptide induced diabetes and induction of insulin autoantibodies (IAA) are dependent on BALB/c genes. This B:9-23 peptide induced diabetes is consistent with MHC class II H-2(d)being necessary for the response to this peptide. Of note Poly I:C induction of diabetes was lost while B:9-23 induction was retained with backcrossing to BALB/c mice. Interaction of genes and environment (antigenic epitope and viral mimic) can be important in the pathogenesis of immune mediated diabetes and activation of the innate immune system (e.g. Poly I:C) may be one key determinant.
Animals↗
Animal models of insulin-dependent diabetes.
Animal models have contributed enormously to study in the field of type 1 diabetes. Perhaps the most intensively studied model is the nonobese diabetic (NOD) mouse, which develops an autoimmune-mediated spontaneous diabetes associated with the development of insulin autoantibodies and insulitis. Accurate measurement of antiislet autoantibodies by radioassay and detection of antigen-specific T cells using major histocompatibility complex tetramers are possible. Various strategies have been developed in preventing diabetes in animal models; a peptide-induced model of type 1 diabetes has been described. Finally, the development of peptide vaccines is hampered by the risk of anaphylaxis in both mouse and humans. In this chapter, methods and strategies to measure antiinsulin autoantibodies, to detect antigen-specific T cells by tetramer analysis, and to prevent diabetes using peptide vaccines are discussed. Along with these topics, a protocol of peptide-induced diabetes and peptide vaccine-induced anaphylaxis are described, serving as a reminder of the potential dangers that could exist in human trials. In summary, animal models have become necessary in the study of type 1 diabetes and provide researchers important tools to conduct studies that could not otherwise be performed in humans.
Amino Acid Sequence↗
Heterophile antibodies masquerade as interferon-alpha in subjects with new-onset type 1 diabetes.
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Animals↗
Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse.
It has been reported that an insulin 2 gene knockout, when bred onto nonobese diabetic (NOD) mice, accelerates diabetes. We produced insulin 1 gene knockout congenic NOD mice. In contrast to insulin 2, diabetes and insulitis were markedly reduced in insulin 1 knockout mice, with decreased and delayed diabetes in heterozygous females and no insulitis and diabetes in most homozygous female mice. Lack of insulitis was found for insulin 1 female homozygous knockout mice at 8, 12, and 37 weeks of age. Despite a lack of insulitis, insulin 1 homozygous knockout mice spontaneously expressed insulin autoantibodies. Administration of insulin peptide B:9-23 of both insulin 1 and 2 to NOD mice induced insulin autoantibodies. Insulin 1 is not the only lymphocytic target of NOD mice. Insulin 1 homozygous knockout islets, when transplanted into recently diabetic wild-type NOD mice, became infiltrated with lymphocytes and only transiently reversed diabetes. These observations indicate that loss of either insulin gene can influence progression to diabetes of NOD mice and suggest that the preproinsulin 1 gene is crucial for the spontaneous development of NOD insulitis and diabetes.
Animals↗
Early oxidative stress in the diabetic kidney: effect of DL-alpha-lipoic acid.
Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The attempts to identify early markers of diabetes-induced renal oxidative injury resulted in contradictory findings. We characterized early oxidative stress in renal cortex of diabetic rats, and evaluated whether it can be prevented by the potent antioxidant, DL-alpha-lipoic acid. The experiments were performed on control rats and streptozotocin-diabetic rats treated with/without DL-alpha-lipoic acid (100 mg/kg i.p., for 3 weeks from induction of diabetes). Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats vs. controls (p <.01) and this increase was partially prevented by DL-alpha-lipoic acid. F(2) isoprostane concentrations (measured by GCMS) expressed per either mg protein or arachidonic acid content were not different in control and diabetic rats but were decreased several-fold with DL-alpha-lipoic acid treatment. Both GSH and ascorbate (AA) levels were decreased and GSSG/GSH and dehydroascorbate/AA ratios increased in diabetic rats vs. controls (p <.01 for all comparisons), and these changes were completely or partially (AA) prevented by DL-alpha-lipoic acid. Superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione transferase, and NADH oxidase, but not catalase, were upregulated in diabetic rats vs. controls, and these activities, except glutathione peroxidase, were decreased by DL-alpha-lipoic acid. In conclusion, enhanced oxidative stress is present in rat renal cortex in early diabetes, and is prevented by DL-alpha-lipoic acid.
Albuminuria↗
Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse.
INTRODUCTION: Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that induces insulin autoantibodies and prevents diabetes in the NOD. However, immunization with peptide without adjuvant may be insufficient to reverse disease or induce long-term tolerance. Furthermore, recent experience has demonstrated the potential dangers of disease exacerbation or anaphylaxis with peptide immunotherapy. METHODS: Combination therapy of B:9-23 with a nondepleting anti-CD4 monoclonal antibody (YTS 177.9) was studied in female NOD mice from 4 through 6 weeks of age. Injections of either B:9-23 in saline, YTS 177.9 antibody, or both peptide and antibody were given to mice. RESULTS: By 52 weeks follow-up, 40% of B:9-23-treated, 100% of YTS177.9-treated, and 70% of B:9-23 and YTS177.9 combination-treated mice remained diabetes-free. IAA, both spontaneous and induced by B:9-23, was almost completely suppressed in mice receiving YTS 177.9. In addition to suppression of IAA expression, anti-B:9-23 peptide antibodies are also suppressed in mice receiving B:9-23 with YTS 177.9, compared to B:9-23 alone. CONCLUSION: A brief course of the nondepleting anti-CD4 monoclonal antibody (YTS 177.9) in NOD mice confers long-term protection from diabetes and insulitis and profoundly blocks spontaneous and B:9-23 peptide-induced insulin autoantibodies.
Adoptive Transfer↗
Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease.
BACKGROUND & AIMS: Asymptomatic children at risk for celiac disease (CD) and seropositive for immunoglobulin A anti-TG autoantibodies (TGAA) may lack small intestinal mucosal changes characteristic of CD. We have followed a group of children with serial testing for TGAA. METHODS: Subjects were a group of at-risk children comprised of infants expressing HLA-DR3 on newborn screening, those with type 1A diabetes, or a first-degree relative of someone with type 1 diabetes. All children participating in the prospective study for development of CD underwent serial testing for TGAA. Data from clinical evaluation and small intestinal biopsy were compared to the TGAA levels followed over time. RESULTS: In 42 children, serial TGAA determinations while on a gluten-containing diet showed levels fluctuating 10-100-fold over 3-12 months. A TGAA index more than 0.5 had a positive predictive value (PPV) for histologic confirmation of CD of 96% (22/23). A TGAA index above the usual cutoff for positivity (0.05) had a PPV of only 76% (28/37). CONCLUSIONS: In children with TGAA seropositivity, the TGAA level varied over time and a higher titer predicted an abnormal biopsy characteristic of CD. A threshold for biopsy for diagnosis of CD could be set higher for screening-identified cases than for clinically identified cases to decrease the frequency of performing "normal" biopsies.
Autoantibodies↗
Absence of the T-bet gene coding for the Th1-related transcription factor does not affect diabetes-associated phenotypes in Balb/c mice.
The T-box expressed in T cells gene (T-bet) is a member of the T-box family of transcription factors. T-bet-deficient mice show normal lymphoid development, but exhibit profound defects in their Th1-mediated immune responses. As the balance between Th1- and Th2-mediated immune responses plays a role in autoimmune-prone diseases, we have investigated the diabetes-related insulin autoantibody (IAA) and cellular immune responses (insulitis), in the absence of Th1 lineage commitment, in T-bet KO Balb/c mice, after immunization with the B9-23 insulin peptide. We have therefore investigated whether absence of the T-bet gene influences diabetes-related phenotypes in Balb/c T-bet KO mice.
Animals↗
Establishing insulin 1 and insulin 2 knockout congenic strains on NOD genetic background.
As insulin is a major autoantigen in autoimmune diabetes and because the insulin gene region locus in humans has been linked to diabetes risk, we have bred insulin gene knockouts onto the NOD mouse. Mice differ from humans in terms that they express two nonallelic genes of insulin. Insulin 2 is the murine homologue of the human insulin gene and is located on mouse chromosome 7. Insulin 1 is thought to have evolved by a gene duplication event, lacks the second intron of the insulin 2 gene, and is located on mouse chromosome 19. The differential thymic expression of the insulin gene may be important for central tolerance induction. Here, we present the initial establishment of congenic knockouts and characterization of the congenic intervals corresponding to insulin 1 and insulin 2 knockout genes on mouse chromosome 19 and 7, respectively.
Animals↗
In vivo expression of B:9-23 peptide/I-A(g7) complex may abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice.
Insulin B chain peptide B:9-23 given to NOD mice decreases the development of diabetes, and phase II trials of an altered peptide ligand of B:9-23 are under way in humans. We have created a gene for the NOD MHC class II beta chain, covalently linked to the B:9-23 peptide. B lymphoma cells transfected with the gene stimulated NOD islet-derived B:9-23 reactive T cell clones in vitro. In this study, we generated an RGD-fiber-mutant adenovirus vector encoding the covalent B:9-23 peptide/I-A(g7) gene (Ad-RGD-B:9-23) to test whether in vivo expression of the gene could protect NOD mice from diabetes. NOD female mice were injected intramuscularly with 5 x 10(8) PFU of Ad-RGD-B:9-23 and empty RGD-adenovirus vector. A single administration of the empty vector did not alter the expression of insulin autoantibodies, but delayed the onset of diabetes in NOD mice. In contrast, Ad-RGD-B:9-23 immunization induced an early expression of insulin autoantibodies, but did not change the disease occurrence compared to control NOD mice. Our results suggest that adenovirus infection could confer protection from diabetes in NOD mice. The in vivo expression of covalent B:9-23 peptide/class II complex by adenovirus gene transfer might activate anti-insulin autoimmunity, resulting in abrogation of the inhibition of diabetes induced by an RGD-fiber-mutant adenovirus vector.
Adenoviridae↗
Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide.
Polyinosinic-polycytidylic acid (PolyIC), a "mimic" of double-stranded viral RNA, can induce diabetes when administered to rats with RT1(u), and immunization of normal H-2(d) mice (e.g., BALB/c) with insulin B:9-23 peptide (but not H-2(b)) results in the rapid induction of insulin autoantibodies. Because a mouse model of PolyIC/antigen-induced diabetes is lacking, we sought to produce insulitis and diabetes with either PolyIC and/or B:9-23 peptide immunization. Simultaneous administration of PolyIC and B:9-23 peptide to BALB/c mice (but with neither alone) induced insulitis. CD4 T lymphocytes predominated within islets, and the mice did not progress to hyperglycemia. Islets with transgene-induced expression of the costimulatory B7-1 molecule have enhanced diabetes susceptibility. Diabetes was frequently induced in B7-1 transgenic mice with H-2(d) in contrast to H-2(b) mice after PolyIC administration. Disease induction was accelerated by adding B:9-23 immunization to PolyIC. These studies demonstrate that "normal" mice have autoreactive T lymphocytes able to rapidly target islets and insulin given appropriate MHC alleles and that a peripherally administered insulin peptide (an altered peptide ligand of which is in clinical trials) can enhance specific anti-islet autoimmunity. These first PolyIC/insulin-induced murine models should provide an important tool to study the pathogenesis of type 1 diabetes with experimental autoimmune diabetes.
Alleles↗
Type 1A diabetes mellitus-associated autoimmunity.
Type 1A diabetes mellitus has become one of the most intensively studied autoimmune disorders, with characterized animal models and extensive prospective studies of the development of anti-islet autoimmunity. It is now possible to predict the development of type 1A diabetes mellitus, beginning with HLA-encoded genetic susceptibility, followed by the development of a series of anti-islet autoantibodies. Prediction primarily is based on the detection of multiple anti-islet autoantibodies reacting with cloned islet antigens. Multiple international workshops fostered the development of specific and sensitive radioassays for autoantibodies reacting with GAD65 (glutamic acid decarboxylase), ICA512 (also termed IA-2, a tyrosine phosphatase-like protein), and insulin. Similar high throughput radioassays have been applied using autoantigens for additional autoimmune disorders including celiac disease and Addison's disease. Relatives of patients with type 1A diabetes mellitus inherit susceptibility to express multiple autoantibodies, and a subset of autoantibody-positive individuals inherit susceptibility to progress to overt disease. This article reviews autoimmune disorders associated with type 1A diabetes mellitus.
Addison Disease↗
Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes.
Type 1 diabetes of both the NOD mouse and man is associated with autoimmunity directed against insulin which is the only beta cell specific autoantigen identified to date. One can use autoantibodies to insulin to predict diabetes, use insulin peptides to create insulin autoantibodies, insulitis and diabetes, and use insulin or its peptides in animal models to prevent diabetes. An expanding set of resources are now available for the development and testing in man of therapies to prevent type 1 diabetes, and a number of trials utilizing insulin peptides are now underway.
Animals↗
Induction of insulin autoantibodies and protection from diabetes with subcutaneous insulin B:9-23 peptide without adjuvant.
Insulin B chain peptide B:9-23 given with incomplete Freund's adjuvant (IFA) subcutaneously to NOD and BALB/c mice induces insulin autoantibodies (IAA). We also found that subcutaneous administration of the peptide without adjuvant induced IAA in normal BALB/c mice. The autoantibodies react with intact insulin and cannot be absorbed by the B:9-23 peptide. With the induction of IAA by the self-peptide without adjuvant, we hypothesized that the peptide given subcutaneously without adjuvant would prevent the development of diabetes mellitus in NOD mice. The peptide B:9-23, when given in standard doses of 100 microg and low doses of 10 microg, protected female NOD mice versus unvaccinated controls from diabetes. Presently, NOD mice vaccinated with the standard dose and the low dose have a 44% and 60% survival, respectively, at 26 weeks compared to controls with a 10% diabetes-free survival at 22 weeks (n = 10 for each group, P < 0.001 for both vaccine doses). As expected, the level of IAA expressed was significantly higher for the vaccinated mice versus the control group. We conclude that insulin B chain peptide B:9-23 can confer protection from diabetes in NOD mice even when administered subcutaneously without adjuvant.
Adjuvants, Immunologic↗