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KMID : 0923620130130050194
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Immune Network
2013 Volume.13 No. 5 p.194 ~ p.198
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Treatment of Autoimmune Diabetes by Inhibiting the Initial Event
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Lee Myung-Shik
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Abstract
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Recent papers have shown that the initial event in the patho-genesis of autoimmune type 1 diabetes (T1D) comprises sensing of molecular patterns released from apoptotic ?-cells by innate immune receptors such as toll-like receptor (TLR). We have reported that apoptotic ?-cells undergoing secondary necrosis called ’late apoptotic’ ?-cells stimulate dendritic cells (DCs) and induce diabetogenic T cell priming through TLR2. The role of other innate immune receptors such as TLR7 or TLR9 in the initiation of T1D has also been suggested. We hypothesized that TLR2 blockade could in-hibit T1D at the initial step of T1D. Indeed, when a TLR2 ago-nist, Pam3CSK4 was administered chronically, the develop-ment of T1D in nonobese diabetic (NOD) mice was inhibited. Diabetogenic T cell priming by DCs was attenuated by chronic treatment with Pam3CSK4, indicating DC tolerance. For the treatment of established T1D, immune tolerance alone is not enough because ?-cell mass is critically reduced. We employed TLR2 tolerance in conjunction with is-let transplantation, which led to reversal of newly established T1D. Dipeptidyl peptidase 4 (DPP4) inhibitors are a new class of anti-diabetic agents that have beneficial effects on ?-cells. We investigated whether a combination of DPP4 in-hibition and TLR2 tolerization could reverse newly estab-lished T1D without islet transplantation. We could achieve normoglycemia by TLR2 tolerization in combination with DPP4 inhibition but not by TLR2 tolerization or DPP4 in-hibition alone. ?-cell mass was significantly increased by combined treatment with TLR2 tolerization and DPP4 inhibition. These results suggest the possibility that a novel strategy of TLR tolerization will be available for the inhibition or treatment of established T1D when combined with meas-ures increasing critically reduced ?-cell mass of T1D pa-tients such as DPP4 inhibition or stem cell technology.
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KEYWORD
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Type 1 diabetes, Autoimmunity, TLR2, Tolerance, DPP4
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