The Journal of Immunology, Vol 156, Issue 12 4916-4924, Copyright © 1996 by American Association of Immunologists

ARTICLES

Inhibition by CTLA4Ig of experimental allergic encephalomyelitis

T Arima, A Rehman, WF Hickey and MW Flye
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can block this interaction and prevent specific T cell activation. The development of fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in susceptible female Lewis rats was optimized by immunization with 20 mg of guinea pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen uniformly resulted in the development of severe clinical neurologic signs of EAE with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the incidence, delayed the onset, and reduced the severity of clinical EAE (p = 0.0002 vs control by the Mann- Whitney U test) enough to completely prevent fatal EAE, whereas treatment with control human IgG had no effect. Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin basic protein and proteolipid protein) by lymph node cells from animals immunized with guinea pig spinal cord 10 days before was also significantly suppressed in vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could be completely prevented by the daily i.p. administration, from day 0 to 10, of exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell-mediated EAE in the rat.

This article has been cited by other articles:

				R Axmann, S Herman, M Zaiss, S Franz, K Polzer, J Zwerina, M Herrmann, J Smolen, and G Schett CTLA-4 directly inhibits osteoclast formation Ann Rheum Dis, November 1, 2008; 67(11): 1603 - 1609. [Abstract] [Full Text] [PDF]

				S. K. O'Neill, Y. Cao, K. M. Hamel, P. D. Doodes, G. Hutas, and A. Finnegan Expression of CD80/86 on B Cells Is Essential for Autoreactive T Cell Activation and the Development of Arthritis J. Immunol., October 15, 2007; 179(8): 5109 - 5116. [Abstract] [Full Text] [PDF]

				T. J. Lang, P. Nguyen, R. Peach, W. C. Gause, and C. S. Via In Vivo CD86 Blockade Inhibits CD4+ T Cell Activation, Whereas CD80 Blockade Potentiates CD8+ T Cell Activation and CTL Effector Function J. Immunol., April 15, 2002; 168(8): 3786 - 3792. [Abstract] [Full Text] [PDF]

				Y. Tada, K. Nagasawa, A. Ho, F. Morito, S. Koarada, O. Ushiyama, N. Suzuki, A. Ohta, and T. W. Mak Role of the Costimulatory Molecule CD28 in the Development of Lupus in MRL/lpr Mice J. Immunol., September 15, 1999; 163(6): 3153 - 3159. [Abstract] [Full Text] [PDF]

				D. C. Lenz, N. A. Wolf, and R. H. Swanborg Strain Variation in Autoimmunity: Attempted Tolerization of DA Rats Results in the Induction of Experimental Autoimmune Encephalomyelitis J. Immunol., August 15, 1999; 163(4): 1763 - 1768. [Abstract] [Full Text] [PDF]

				P. J. Perrin, C. H. June, J. H. Maldonado, R. B. Ratts, and M. K. Racke Blockade of CD28 During In Vitro Activation of Encephalitogenic T Cells or After Disease Onset Ameliorates Experimental Autoimmune Encephalomyelitis J. Immunol., August 1, 1999; 163(3): 1704 - 1710. [Abstract] [Full Text] [PDF]

				A. J. Oliveira-dos-Santos, A. Ho, Y. Tada, J. J. Lafaille, S. Tonegawa, T. W. Mak, and J. M. Penninger CD28 Costimulation Is Crucial for the Development of Spontaneous Autoimmune Encephalomyelitis J. Immunol., April 15, 1999; 162(8): 4490 - 4495. [Abstract] [Full Text] [PDF]

				Y. Tada, K. Nagasawa, A. Ho, F. Morito, O. Ushiyama, N. Suzuki, H. Ohta, and T. W. Mak CD28-Deficient Mice Are Highly Resistant to Collagen-Induced Arthritis J. Immunol., January 1, 1999; 162(1): 203 - 208. [Abstract] [Full Text] [PDF]