Beginning at the time of insulitis (7 wk age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This does not result either or thymic involution is long lasting, i.e., persists until diabetes onset (24 age). We previously proposed that it represents form anergy predisposes to onset. hypothesis was tested present study by further investigating mechanism responsible for NOD determining...

We tested the hypothesis that alterations in intestinal microbiota are linked with progression of type 1 diabetes (T1D). Herein, we present results from a study performed subjects islet autoimmunity living U.S. High-throughput sequencing bacterial 16S rRNA genes and adjustment for sex, age, autoantibody presence, HLA indicated gut microbiomes seropositive differed those autoantibody-free first-degree relatives (FDRs) abundance four taxa. Furthermore, autoantibodies, seronegative FDRs,...

OBJECTIVE Dysbiosis of the gut microbiota has been linked to disease pathogenesis in type 1 diabetes, yet functional consequences host this dysbiosis are unknown. We investigated interactions between and associated with diabetes risk. RESEARCH DESIGN AND METHODS performed a cross-sectional analysis stool samples from subjects recent-onset (n = 33), islet autoantibody–positive 17), low-risk autoantibody-negative 29), healthy 22). Metaproteomic was used identify gut- pancreas-derived microbial...

Virus infection is hypothesized to be an important environmental "trigger" of type 1 diabetes in humans. We used the BBDR rat model investigate relationship between viral and autoimmune diabetes. rats are diabetes-free Ab-free housing, but disease develops approximately 30% infected with Kilham virus (KRV) through a process that does not involve pancreatic beta cells. Pretreatment polyinosinic-polycytidylic (poly(I:C)), ligand TLR3, acts synergistically induce 100% KRV-infected rats. The...

Microbes were hypothesized to play a key role in the progression of type 1 diabetes (T1D). We used LEW1.WR1 rat model Kilham virus (KRV)-induced T1D test hypothesis that intestinal microbiota is involved mechanism leading islet destruction. Treating rats with KRV and combination trimethoprim sulfamethoxazole (Sulfatrim) beginning on day infection protected from insulitis T1D. Pyrosequencing bacterial 16S rRNA quantitative RT-PCR indicated resulted transient increase abundance Bifidobacterium...

Inflammatory cytokines, particularly those produced by Th1 type lymphocytes, are hypothesized to play a major role in the pathogenesis of autoimmune diseases. The present studies investigated this hypothesis BB rat. Diabetes-prone (DP) rats develop spontaneous hyperglycemia and thyroiditis. Coisogenic diabetes-resistant (DR) do not either disorder spontaneously, but both diseases induced depletion RT6+ T cells. Reverse transcriptase-PCR was used measure mRNA encoding 1 2 cytokines. In DP...

In nonobese diabetic (NOD) mice, T cells play a major role in mediating autoimmunity against pancreatic islet beta-cells. We and others previously reported that age-related alterations the thymic peripheral cell repertoire function occur prediabetic NOD mice. To study mechanism responsible for these alterations, we examined whether defect exists thymus of mice at level TCR-mediated signaling after activation by Con A anti-CD3. found thymocytes from respond weakly to A- anti-CD3-induced...

Abstract Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but mechanisms underlying this putative association unknown. To investigate role viruses diabetes, we used a model viral induction autoimmune genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop viral-Ab-free environments, ∼25% animals infected parvovirus Kilham rat virus (KRV) via mechanism that does involve β cell infection. Using model,...

Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D).Our objective was to evaluate safety and effects therapy with anti-inflammatory serum protein α1-antitrypsin (AAT) on islet function innate immunity recent-onset patients.This an open-label phase I trial at Barbara Davis Center for Childhood Diabetes, University Colorado Denver.Twelve recently diagnosed subjects T1D detectable C-peptides were included study.Eight consecutive weekly infusions 80...

We recently hypothesized that the intestinal microbiota and innate immune system play key roles in mechanism of Kilham Rat Virus-induced type 1 diabetes LEW1.WR1 rat. used this animal model to test hypothesis maternal therapy with short-chain fatty acids can modulate reverse virus-induced proinflammatory responses rat offspring. observed administration breeders via drinking water prior pregnancy further treatment offspring after weaning led disease amelioration. In contrast, rats were...

We tested the hypothesis that altered Toll-like receptor (TLR) signaling may be involved in early stages of type 1 diabetes (T1D). To do so, we analyzed TLR-induced interleukin (IL)-1β and IL-6 responses freshly isolated peripheral blood mononuclear cells (PBMNCs) from seropositive compared with seronegative subjects. Similar frequencies myeloid dendritic (mDCs), plasmacytoid DCs (pDCs), monocytes were observed Subjects autoantibodies had increased proportions expressing IL-1β ex vivo....

RIP-B7.1 transgenic mice express B7.1 costimulatory molecules in pancreatic islets and develop diabetes after treatment with polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA agonist of Toll-like receptor (TLR) 3 retinoic acid-inducible protein I. We used this model to investigate the role TLR pathways intestinal microbiota disease progression. homozygous for targeted disruption TLR9, TLR3, myeloid differentiation factor-88 (MyD88), most wild-type housed under...

Viruses are believed to contribute the pathogenesis of autoimmune type 1A diabetes in humans. This pathogenic process can be modeled BBDR rat, which develops pancreatic insulitis and 1A-like after infection with Kilham's rat virus (RV). The mechanism is unknown, but does not involve islets. We first documented that RV rats induces diabetes, whereas its close homologue H-1 not. Both viruses induced similar humoral cellular immune responses host, only also caused a decrease splenic...

Rat models of diabetes have emerged as a powerful experimental tool for addressing the role microbial pathogens in mechanism autoimmune diabetes. We used biobreeding resistant and LEW1.WR1 rat to identify virus-induced innate immunity type 1 diabetes.Groups rats 21-25 days age were left untreated, injected i.p. with 1×10(7) PFU Kilham virus (KRV) only, or 1-3 µg/g body-weight-purified toll-like receptor agonists on three consecutive infected KRV following day. Spleens pancreatic lymph nodes...