The Hsp60 peptide p277 enhances anti-CD3 mediated diabetes remission in non-obese diabetic mice.

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells leading to inadequate glycemic control. Trials with immunomodulatory monotherapies have shown that the disease course can in principle be altered. The observed preservation of endogenous insulin secretion however is typically transient and chronic treatment is often associated with significant side effects.

BDC12-4.1 T-cell receptor transgenic insulin-specific CD4 T cells are resistant to in vitro differentiation into functional Foxp3+ T regulatory cells.

The infusion of ex vivo-expanded autologous T regulatory (Treg) cells is potentially an effective immunotherapeutic strategy against graft-versus-host disease (GvHD) and several autoimmune diseases, such as type 1 diabetes (T1D). However, in vitro differentiation of antigen-specific T cells into functional and stable Treg (iTreg) cells has proved challenging. As insulin is the major autoantigen leading to T1D, we tested the capacity of insulin-specific T-cell receptor (TCR) transgenic CD4(+) T cells of the BDC12-4.

Direct infection of dendritic cells during chronic viral infection suppresses antiviral T cell proliferation and induces IL-10 expression in CD4 T cells.

Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence. This report highlights the relationship between enhanced viral tropism for DCs and the induction of IL-10 in CD4 T cells, which we identify as the most frequent IL-10-expressing cell type in chronic LCMV infection.

Combination therapy with an anti-IL-1β antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.

Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic β-cells. As a proinflammatory cytokine produced by β-cells or macrophages, interleukin-1β (IL-1β) represents a potential therapeutic target in diabetes. We reasoned IL-1β blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3.

CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes.

Previous cross-sectional analyses demonstrated that CD8(+) and CD4(+) T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4(+) T-cell cytokine production and autoreactive CD8(+) T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4(+) T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD.

Temporal intra-individual variation of immunological biomarkers in type 1 diabetes patients: implications for future use in cross-sectional assessment.

Multiple immune parameters such as frequencies of autoreactive CD4(+), CD8(+) T-cells and CD4(+)CD25(+)Foxp3(+) T-cells have been explored as biomarkers in human T1D. However, intra-individual temporal variation of these parameters has not been assessed systematically over time. We determined the variation in each of these parameters in a cohort of T1D and healthy donors (HDs), at monthly intervals for one year.

Transient B-cell depletion with anti-CD20 in combination with proinsulin DNA vaccine or oral insulin: immunologic effects and efficacy in NOD mice.

A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine.

Diminished AMPK signaling response to fasting in thioredoxin-interacting protein knockout mice.

Thioredoxin-interacting protein (Txnip) knockout (TKO) mice exhibit impaired response to fasting. Herein, we showed that activation of adenine monophosphate-activated protein kinase and cellular AMP levels were diminished in the heart and soleus muscle but not in gastrocnemius muscle of fasting TKO mice. Similarly, glycogen content in fasted TKO mice was increased in oxidative muscles but was not different in glycolytic muscles.

Txnip balances metabolic and growth signaling via PTEN disulfide reduction.

Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue).