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Transient Upregulation of Indoleamine 2,3-Dioxygenase in Dendritic Cells by Human Chorionic Gonadotropin Downregulates Autoimmune Diabetes

¹ Julia McFarlane Diabetes Research Centre, Department of Biochemistry and Molecular Biology, University of Calgary, Canada
² Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Canada

Address correspondence and reprint requests to Yang Yang, University of Calgary, Department of Biochemisty and Molecular Biology, Calgary, Alberta T2N 4N1, Canada. E-mail: yyang{at}ucalgary.ca

Abbreviations: 1-MT, 1-methyl-tryptophan; 3,4-DAA, N-(3,4,-dimethoxycinnamoyl) anthralic acid; APC, antigen-presenting cell; CFSE, carboxyfluorescein diacetate succinimidyl ester; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; hCG, human chorionic gonadotropin; IDO, indoleamine 2,3-dioxygenase; IFN-, -interferon; IL, interleukin; MHC, major histocompatibility complex

OBJECTIVE—Pregnancy induces a state of immunological tolerance that aims at suppressing immune responses against the fetus and has been linked to temporal remission of preexisting autoimmune disorders. To understand the mechanisms of this reversible immune regulation, we investigated the role of a key pregnancy hormone, human chorionic gonadotropin (hCG), in immune tolerance against autoimmune type 1 diabetes in nonobese diabetic (NOD) mice.

RESEARCH DESIGN AND METHODS—We injected hCG into cytokine gene–deficient NOD mice and evaluated the effects of hCG administration on T-cells and dendritic cells (DCs).

RESULTS—We show that administration of hCG to NOD mice inhibits both the activation of diabetogenic CD4⁺ and CD8⁺ T-cells, in vitro and in vivo, and the progression of type 1 diabetes by upregulating the expression of indoleamine 2,3-dioxygenase (IDO) in DCs. IDO upregulation is transient and declined shortly after hCG withdrawal. DC depletion restores the diabetetogenic activity of splenic T-cells from hCG-treated mice, and inhibition of IDO activity by 1-methyl-tryptophan abrogates the hCG-induced T-cell suppression and resistance to type 1 diabetes.

CONCLUSIONS—We propose that hCG-induced upregulation of IDO in DCs plays a major role in pregnancy-associated resistance to autoimmunity.

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