The Journal of Experimental Medicine
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Published 1 August 2005. doi:10.1084/jem.20051060
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 3, 445-455
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ARTICLE

 Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis

Niklas Beyersdorf1, Stefanie Gaupp2, Karen Balbach1, Jens Schmidt2, Klaus V. Toyka2, Chia-Huey Lin1, Thomas Hanke3, Thomas Hünig1, Thomas Kerkau1, and Ralf Gold2,4

1 Institute for Virology and Immunobiology, University of Würzburg
2 Department of Neurology, University Hospital Würzburg, D-97078 Würzburg, Germany
3 TeGenero ImmunoTherapeutics AG, D-97076 Würzburg, Germany
4 Institute for MS Research, University of Göttingen and Gemeinnützige Hertie Stiftung, D-37073 Göttingen, Germany

CORRESPONDENCE Thomas Kerkau: kerkau{at}mail.uni-wuerzburg.de

CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.

Abbreviations used: AT, adoptive transfer EAE; CFSE, carboxyfluorescein diacetate succinimidyl ester; CNS, central nervous system; CTLA-4, CTL-associated antigen 4; DA, Dark Agouti; EAE, experimental autoimmune encephalomyelitis; gpMBP, guinea pig MBP; LNC, lymph node cell; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; T reg cell, regulatory T cell; Tconv cell, conventional T cell.

N. Beyersdorf, S. Gaupp, T. Kerkau, and R. Gold contributed equally to this work.

S. Gaupp's present address is Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.


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