Endosomal Sequestration of TLR4 Antibody Induces Myeloid-Derived Suppressor Cells and Reverses Acute Type 1 Diabetes.

We previously showed that treating NOD mice with an agonistic monoclonal anti-TLR4/MD2 antibody (TLR4-Ab) reversed acute type 1 diabetes (T1D). Here, we show that TLR4-Ab reverses T1D by induction of myeloid-derived suppressor cells (MDSCs). Unbiased gene expression analysis after TLR4-Ab treatment demonstrated upregulation of genes associated with CD11b+Ly6G+ myeloid cells and downregulation of T-cell genes.

Enoxacin Up-Regulates MicroRNA Biogenesis and Down-Regulates Cytotoxic CD8 T-Cell Function in Autoimmune Cholangitis.

Background And Aims: Primary biliary cholangitis (PBC) is a prototypical organ-specific autoimmune disease that is mediated by autoreactive T-cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune-directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune diseases. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC).

Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy.

We show here that soluble CD137 (sCD137), the alternately spliced gene product of , effectively treats acute type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. sCD137 significantly delayed development of end-stage disease, preserved insulin+ islet beta cells, and prevented progression to end-stage T1D in some mice. We demonstrate that sCD137 induces CD4+ T cell anergy, suppressing antigen-specific T cell proliferation and IL-2/IFN-γ secretion.

CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice.

We previously reported that CD137 (encoded by ) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed.

Reversal of New-Onset Type 1 Diabetes With an Agonistic TLR4/MD-2 Monoclonal Antibody.

Type 1 diabetes (T1D) is currently an incurable disease, characterized by a silent prodromal phase followed by an acute clinical phase, reflecting progressive autoimmune destruction of insulin-producing pancreatic β-cells. Autoreactive T cells play a major role in β-cell destruction, but innate immune cell cytokines and costimulatory molecules critically affect T-cell functional status. We show that an agonistic monoclonal antibody to TLR4/MD-2 (TLR4-Ab) reverses new-onset diabetes in a high percentage of NOD mice.

Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells.

Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells transfer biliary disease.

Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice.

Nonobese diabetic (NOD) mice are genetically programmed to spontaneously develop type one diabetes (T1D). Multiple Insulin dependent diabetes (Idd) genetic loci have been identified but their functional effects are mostly poorly understood. TnfsfR9, expressing the protein product CD137, is a strong candidate gene in the Idd9.

The B10 Idd9.3 locus mediates accumulation of functionally superior CD137(+) regulatory T cells in the nonobese diabetic type 1 diabetes model.

CD137 is a T cell costimulatory molecule encoded by the prime candidate gene (designated Tnfrsf9) in NOD.B10 Idd9.3 congenic mice protected from type 1 diabetes (T1D).

The non-obese diabetic (NOD) mouse as a model of human type 1 diabetes.

The non-obese diabetic (NOD) mouse spontaneously develops type 1 diabetes (T1D) and has thus served as a model for understanding the genetic and immunological basis, and treatment, of T1D. Since its initial description in 1980, however, the field has matured and recognized that prevention of diabetes in NOD mice (i.e.

Modulating protective and pathogenic CD4+ subsets via CD137 in type 1 diabetes.

CD137 (TNFRSF9) is an activation-inducible T-cell costimulatory molecule and a member of the tumor necrosis factor (TNF) receptor superfamily. Cd137 is also a candidate gene (in the Idd9.3 interval) for autoimmune diabetes in NOD mice.

Chimeric HIV-1 and HIV-2 lentiviral vectors with added safety insurance.

Lentiviruses are unique in their ability to infect both dividing and non-dividing cells. This makes the vectors derived from them particularly useful for gene transfer into non-dividing cells, including stem cells. Lentiviral vectors are becoming the vectors of choice for si/shRNA delivery.

Population distribution of the functional caspase-12 allele.

Members of the caspase family can be important for apoptosis or inflammation, but the role of caspase-12 (CASP12 or CSP12) is unclear. Although most humans lack a functional caspase-12, the Csp 12-L variant, previously found only among people of African descent, produces a full-length proenzyme and increases the risk of sepsis. In this study, Csp 12-L allele frequency ranged from 3.