19 research outputs found
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes.
β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells
CD45 ligation expands Tregs by promoting interactions with DCs
Regulatory T cells (Tregs), which express CD4 and FOXP3, are critical for modulating the immune response and promoting immune tolerance. Consequently, methods to expand Tregs for therapeutic use are of great interest. While transfer of Tregs after massive ex vivo expansion can be achieved, in vivo expansion of Tregs would be more practical. Here, we demonstrate that targeting the CD45 tyrosine phosphatase with a tolerogenic anti-CD45RB mAb acutely increases Treg numbers in WT mice, even in absence of exogenous antigen. Treg expansion occurred through substantial augmentation of homeostatic proliferation in the preexisting Treg population. Moreover, anti-CD45RB specifically increased Treg proliferation in response to cognate antigen. Compared with conventional T cells, Tregs differentially regulate their conjugation with DCs. Therefore, we determined whether CD45 ligation could alter interactions between Tregs and DCs. Live imaging showed that CD45 ligation specifically reduced Treg motility in an integrin-dependent manner, resulting in enhanced interactions between Tregs and DCs in vivo. Increased conjugate formation, in turn, augmented nuclear translocation of nuclear factor of activated T cells (NFAT) and Treg proliferation. Together, these results demonstrate that Treg peripheral homeostasis can be specifically modulated in vivo to promote Treg expansion and tolerance by increasing conjugation between Tregs and DCs
A Frequency Selection Method Based on the Pole Characteristics
Due to the heavy jamming band of high frequency, frequency selecting strategies are serious issues for the system designed to achieve its best performance. Pole is independent of the direction and polarization of the incident wave, but the residue corresponding to the pole is related to the direction and polarization of the incident wave. And the value of residue is proportional to the value of the pole. This paper chooses the frequency which can maximize the residue in the high-frequency band as the optimal frequency for accurate extraction. The simulation result of a large number of ship targets shows remarkable rise in average recognition rate by using this method, compared with the average recognition rate of randomly selected frequency
Anti-CD20 treatment prolongs syngeneic Islet graft survival and delays the onset of recurrent autoimmune diabetes
Type 1 diabetes is an autoimmune disease characterized by T cell–mediated destruction of pancreatic islet beta cells. Pancreatic islet transplantation with long-term immunosuppressive drug treatment is an accepted therapeutic option for patients with type 1 diabetes suffering from disabling hypoglycemia on insulin treatment. Here we investigated the replacement of immunosuppressive drug treatment with immune tolerance establishment induced by temporary B cell–depletion therapy for islet transplantation. The result suggested that the combined therapy of B cell depletion and syngeneic islet transplantation may reverse the disease in hCD20/NOD mice
Anti-CD20 Treatment Prolongs Syngeneic Islet Graft Survival and Delays the Onset of Recurrent Autoimmune Diabetes
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Immune therapy and β-cell death in type 1 diabetes.
Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of β-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death