HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, X. X. Articles by Strom, T. B. Search for Related Content PubMed PubMed Citation Articles by Zheng, X. X. Articles by Strom, T. B.

IL-2 Receptor-Targeted Cytolytic IL-2/Fc Fusion Protein Treatment Blocks Diabetogenic Autoimmunity in Nonobese Diabetic Mice¹

Xin Xiao Zheng^2,*, Alan W. Steele^2,*, Wayne W. Hancock, Kensaku Kawamoto^*, Xian Chang Li^*, Peter W. Nickerson^*, Yongsheng Li^*, Yan Tian^* and Terry B. Strom^3,*

^* Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Leukosite Inc., Cambridge, MA 02142

High affinity IL-2R⁵ is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL-2R is an attractive therapy for many T cell-dependent cytopathic disease processes. A variety of rodent mAbs directed against the -chain of the IL-2R, as well as IL-2 fusion toxins, have been used in animals and humans to achieve selective immunosuppression. Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein. This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t_1/2 of 25 h following systemic administration. To subsequently explore the mechanisms of the antidiabetogenic effects of IL-2/Fc, we have mutated the FcR binding and complement C1q binding (Fc^-/-) domains of the Fc fragment to render the Fc unable to direct Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. In a model of passive transfer of diabetes in nonobese diabetic mice, lytic IL-2/Fc, but not nonlytic IL-2/Fc^-/-, exhibited striking antidiabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a new therapeutic approach for selective targeting of auto and alloimmune T cells.

This article has been cited by other articles:

				M. J. Benson, S. R. Dillon, E. Castigli, R. S. Geha, S. Xu, K.-P. Lam, and R. J. Noelle Cutting Edge: The Dependence of Plasma Cells and Independence of Memory B Cells on BAFF and APRIL J. Immunol., March 15, 2008; 180(6): 3655 - 3659. [Abstract] [Full Text] [PDF]

				R. E. Burden, P. Snoddy, R. J. Buick, J. A. Johnston, B. Walker, and C. J. Scott Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L-like proteases in tumor microenvironment Mol. Cancer Ther., March 1, 2008; 7(3): 538 - 547. [Abstract] [Full Text] [PDF]

				M. Koulmanda, E. Budo, S. Bonner-Weir, A. Qipo, P. Putheti, N. Degauque, H. Shi, Z. Fan, J. S. Flier, H. Auchincloss Jr., et al. Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts PNAS, August 7, 2007; 104(32): 13074 - 13079. [Abstract] [Full Text] [PDF]

				A. Sanchez-Fueyo, M. Weber, C. Domenig, T. B. Strom, and X. X. Zheng Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance J. Immunol., March 1, 2002; 168(5): 2274 - 2281. [Abstract] [Full Text] [PDF]

				X. C. Li, A. Ima, Y. Li, X. X. Zheng, T. R. Malek, and T. B. Strom Blocking the Common {gamma}-Chain of Cytokine Receptors Induces T Cell Apoptosis and Long-Term Islet Allograft Survival J. Immunol., February 1, 2000; 164(3): 1193 - 1199. [Abstract] [Full Text] [PDF]