Program

PO4-3-43

Suppressive effects of LAT1 specific inhibitor on allergy disease

[Speaker] Keitaro Hayashi:1
[Co-author] Osamu Kaminuma:2, Tomoe Nishimura:3, Promsuk Jutabha:1, Hitoshi Endo:4, Tomoe Fujita:1, Naohiko Anzai:1,5
1:Dept. Pharmacol. and Toxicol., Dokkyo Med. Univ. Sch. Med., Japan, 2:Center Life Sci. Res. Univ. Yamanashi, Japan, 3:Allergy Immunol. Proj. Tokyo Metropol. Inst. Med. Sci., Japan, 4:J-Pharma Co., Ltd, Japan, 5:Dept. Pharmacol. Chiba Univ. Grad. Sch. of Med., Japan

LAT1 (SLC7A5) is a transporter that incorporates essential amino acids into cells. LAT1 has been considered to have an important role for cancer growth, but the function of LAT1 in normal tissues remains unknown. We characterized LAT1 as a major transporter of amino acids for the immune reactions in activated human T cells. Although LAT1 expression was not detected in freshly isolated human T cells, full activation of primary T cells triggered the induction of LAT1 expression. Attenuation of the LAT1 function by JPH203, a specific inhibitor of LAT1, in human T cells suppressed uptake of essential amino acids and immunological reactions. Furthermore, JPH203 exhibited significant therapeutic effects on T cell-induced allergic dermatitis and rhinitis in mice. We also found LAT1 inhibition leads to activation of ATF4, the suppression of energy metabolism and alters the expression of cell cycle-associated proteins, which are considered to be mechanisms by which human T cells put a brake on the cellular metabolism. Our results suggest that pharmacological inhibition of LAT1 is a novel, potentially therapeutic approach for treating hypersensitive immune reaction.
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