Ž . Journal of Neuroimmunology 96 1999 158–166 Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis Meike Schaub a , Shohreh Issazadeh a , Thomas H.W. Stadlbauer a , Robert Peach b , Mohamed H. Sayegh a , Samia J. Khoury a, ) a Brigham and Women’s Hospital, HarÕard Medical School, 77 Louis Pasteur AÕenue, Boston, MA 02115, USA b Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA Received 30 October 1998; received in revised form 27 January 1999; accepted 3 February 1999 Abstract Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune en- Ž . cephalomyelitis EAE . However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration Ž . Ž . of either MR1 to block CD40L or CTLA4Ig to block B7 after immunization or after the first attack protects from EAE. Treatment with a combination of CTLA4Ig and MR1 provides additive protection, and is associated with complete absence of mononuclear cell infiltrates in the central nervous system, and marked suppression of proliferation of primed T cells in the periphery. Selective B7-1 blockade did not protect from EAE. These observations have implications for therapy of autoimmune diseases. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Rodent; EAErMS; Tolerancersuppression; Co-stimulatory molecules; In vivo animal models 1. Introduction Ž . Experimental autoimmune encephalomyelitis EAE is an inflammatory disease of the central nervous system Ž . CNS that has been used as the animal model for the human disease multiple sclerosis. EAE can be induced in a number of species by immunization with myelin basic Ž . protein MBP or other myelin antigens and adjuvant Ž . Kies, 1973 . Autoreactive CD4 q T cells play a key role Ž in the pathogenesis of this autoimmune disorder Zamvil . and Steinman, 1990 , and are therefore a principal target for therapeutic strategies to prevent disease. Blockade of Ž CD28-B7 Cross et al., 1995; Khoury et al., 1995; Kuchroo . et al., 1995; Miller et al., 1995; Perrin et al., 1995 or Ž . CD40L-CD40 Gerritse et al., 1996 prevents induction of murine EAE. Delayed CD28-B7 blockade has also been shown to be effective in preventing relapses and epitope Ž . spreading in the mouse model Miller et al., 1995 . The effect of CD40L blockade after disease onset or to prevent ) Corresponding author. Tel.: q1-617-5255370; Fax: q1-617- 5255252; E-mail: khoury@cnd.bwh.harvard.edu relapses in EAE is unknown. Furthermore, while simulta- neous blockade of CD28-B7 and CD40L-CD40 has been Ž . shown to be synergistic in transplant Larsen et al., 1996 Ž . and lupus Daikh et al., 1997 models, this has not been investigated in EAE. These are clinically relevant issues to patients with multiple sclerosis. In this report, we demon- strate for the first time that concomitant blockade of CD28-B7 and CD40L-CD40 interactions prevents as well as ameliorates ongoing EAE, and is effective in preventing relapses. These observations are particularly relevant be- cause human phase one trials have been initiated using anti-CD40L or CTLA4Ig to treat autoimmune diseases Ž . Sayegh and Turka, 1998 . 2. Materials and methods 2.1. Mice Ž . Female PLrJ = SJL F1 mice were obtained from The Ž . Jackson Laboratory Bar Harbor, ME at the age of 6–8 weeks. The mice were 10–12 weeks old when experiments were started. 0165-5728r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0165-5728 99 00022-3