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Rabbit Polyclonal Mouse Antithymocyte Globulin Administration Alters Dendritic Cell Profile and Function in NOD Mice to Suppress Diabetogenic Responses ¹

Yanfei Huang^*, Matthew Parker, Changqing Xia, Ruihua Peng, Clive Wasserfall, Tracy Clarke, Lizhen Wu^*, Tayseer Chowdhry^*, Martha Campbell-Thompson, John Williams, Michael Clare-Salzler, Mark A. Atkinson and Karl L. Womer^2,*

^* Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21204; Department of Pathology, University of Florida School of Medicine, Gainesville, FL 32611; and Genzyme, Framingham, MA 01701

Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8^– predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4⁺ T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4⁺ T cells with splenic cells from newly diabetic NOD mice into NOD.RAG^–/– mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants K08DK66319, 394288, 394210, DK063422 from the National Institutes of Health, by the Medical Research Service, Department of Veterans Affairs, the Keene Family Professorship, Genzyme Corporation, and the Juvenile Diabetes Research Foundation International.

² Address correspondence and reprint requests to Dr. Karl L. Womer, Department of Medicine, Ross 947, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21204. E-mail address: kwomer1{at}jhmi.edu

³ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T; PLN, pancreatic lymph node; ATG, antithymocyte globulin; mATG, mouse ATG; ILN, inguinal lymph node; 7-AAD, 7-aminoactinomycin D; PDCA, plasmacytoid DC Ag-1.