A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

被引:49
作者
Gommerman, JL
Giza, K
Perper, S
Sizing, I
Ngam-Ek, A
Nickerson-Nutter, C
Browning, JL
机构
[1] Biogen Inc, Dept Exploratory Sci, Cambridge, MA 02142 USA
[2] Biogen Inc, Dept Pharmacol, Cambridge, MA 02142 USA
关键词
D O I
10.1172/JCI200318648
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTalphabeta binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin-free models was associated with defects in T cell responses and migration. When the DO11.10T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.
引用
收藏
页码:755 / 767
页数:13
相关论文
共 55 条
[1]   Expression of lymphotoxin-beta (LT-β) in chronic inflammatory conditions [J].
Agyekum, S ;
Church, A ;
Sohail, M ;
Krausz, T ;
Van Noorden, S ;
Polak, J ;
Cohen, J .
JOURNAL OF PATHOLOGY, 2003, 199 (01) :115-121
[2]   Lymphotoxins and cytomegalovirus cooperatively induce interferon-β, establishing host-virus detente [J].
Benedict, CA ;
Banks, TA ;
Senderowicz, L ;
Ko, M ;
Britt, WJ ;
Angulo, A ;
Ghazal, P ;
Ware, CF .
IMMUNITY, 2001, 15 (04) :617-626
[3]   Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection [J].
Bertram, EM ;
Lau, P ;
Watts, TH .
JOURNAL OF IMMUNOLOGY, 2002, 168 (08) :3777-3785
[4]  
Browning JL, 1997, J IMMUNOL, V159, P3288
[5]   LYMPHOTOXIN-BETA, A NOVEL MEMBER OF THE TNF FAMILY THAT FORMS A HETEROMERIC COMPLEX WITH LYMPHOTOXIN ON THE CELL-SURFACE [J].
BROWNING, JL ;
NGAMEK, A ;
LAWTON, P ;
DEMARINIS, J ;
TIZARD, R ;
CHOW, EPC ;
HESSION, C ;
OBRINEGRECO, B ;
FOLEY, SF ;
WARE, CF .
CELL, 1993, 72 (06) :847-856
[6]   Visualization of lymphotoxin-β and lymphotoxin-β receptor expression in mouse embryos [J].
Browning, JL ;
French, LE .
JOURNAL OF IMMUNOLOGY, 2002, 168 (10) :5079-5087
[7]   Activated CD8+T cells in secondary progressive MS secrete lymphotoxin [J].
Buckle, GJ ;
Höllsberg, P ;
Hafler, DA .
NEUROLOGY, 2003, 60 (04) :702-705
[8]   BOTH RAT AND MOUSE T-CELL RECEPTORS SPECIFIC FOR THE ENCEPHALITOGENIC DETERMINANT OF MYELIN BASIC-PROTEIN USE SIMILAR V-ALPHA AND V-BETA CHAIN GENES EVEN THOUGH THE MAJOR HISTOCOMPATIBILITY COMPLEX AND ENCEPHALITOGENIC DETERMINANTS BEING RECOGNIZED ARE DIFFERENT [J].
BURNS, FR ;
LI, XO ;
SHEN, N ;
OFFNER, H ;
CHOU, YK ;
VANDENBARK, AA ;
HEBERKATZ, E .
JOURNAL OF EXPERIMENTAL MEDICINE, 1989, 169 (01) :27-39
[9]   UP-REGULATION AND COEXPRESSION OF ADHESION MOLECULES CORRELATE WITH RELAPSING AUTOIMMUNE DEMYELINATION IN THE CENTRAL-NERVOUS-SYSTEM [J].
CANNELLA, B ;
CROSS, AH ;
RAINE, CS .
JOURNAL OF EXPERIMENTAL MEDICINE, 1990, 172 (05) :1521-1524
[10]   Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation [J].
Cella, M ;
Scheidegger, D ;
PalmerLehmann, K ;
Lane, P ;
Lanzavecchia, A ;
Alber, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (02) :747-752