Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model.
Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that CD28-B7 blockade by systemic administration of CTLA4Ig prevents actively induced EAE. Since CTLA4Ig binds to both B7-1 and B7-2, we used a mutant form of CTLA4Ig (CTLA4IgY100F) that binds only B7-1, to study the role of B7-1 blockade in this model. Such a reagent avoids the potential of signaling by mAbs. Systemic administration of CTLA4IgY100F in several dosing regimens did not protect from EAE, and in some protocols worsened disease, while CTLA4Ig was always protective. In contrast, systemic injection of APCs preincubated ex vivo with the encephalitogenic peptide of myelin basic protein and either CTLA4Ig or CTLA4IgY100F protected recipients from disease. In vitro studies confirmed the in vivo observations and showed that primed lymph node cells from protected animals had decreased proliferative responses to myelin basic protein as compared with controls, while lymphocytes from animals treated with systemic CTLA4gY100F did not. More importantly, systemic administration of CTLA4IgY100F abrogated the protective effect of ex vivo treated APCs. These data suggest an important regulatory role for B7-1, perhaps through binding to CTLA4, in this model of EAE. Understanding the role and mechanisms of selective blockade of costimulatory molecules has implications for therapy of autoimmune disease.
Gallon
L
L
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chandraker
A
A
Issazadeh
S
S
Peach
R
R
Linsley
P S
PS
Turka
L A
LA
Sayegh
M H
MH
Khoury
S J
SJ
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007111:Immunity, Cellular; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018122:B7-1 Antigen; D018106:CD28 Antigens