Essential role of TGF-beta in the natural resistance to experimental allergic encephalomyelitis in rats.
Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease induced in susceptible rat strains by a single immunization with myelin basic protein (MBP). The Lewis (LEW) strain is susceptible to disease induction while the Brown Norway (BN) strain is resistant. This resistance involves non-MHC genes since congenic BN-1L rats, with LEW MHC on a BN-derived background, are also resistant. In the present study we show that, upon immunization with MBP, the non-MHC-encoded resistance to develop clinical EAE in BN-1L rats is associated with a decreased production of IFN-gamma. This may be due to a difference between LEW and BN-1L rats in their ability to produce regulatory cytokines such as IL-4, IL-10 and TGF-beta. In comparison to LEW rats, immune lymph node cells from BN-1L rats express an increased amount of IL-4 mRNA but produce less IL-10. Furthermore, the sera from BN-1L rats contain higher amounts of active TGF-beta1. Therefore, we have investigated the involvement of IL-4 and TGF-beta in the resistance of BN-1L rats to develop EAE using neutralizing mAb. Neutralization of TGF-beta, but not IL-4, renders BN-1L rats susceptible to clinical EAE without affecting the proliferation or the cytokine repertoire of immune lymph node cells. With respect to the origin of the endogenous TGF-beta production, we excluded the involvement of CD8 T cells and discuss a possible role of platelets and of CD4 T cells exhibiting the CD45RC(low) phenotype.
Cautain
B
B
INSERM U28, Institut Fédératif de recherche 30, and Université Paul Sabatier, Toulouse, France.
Damoiseaux
J
J
Bernard
I
I
van Straaten
H
H
van Breda Vriesman
P
P
Boneu
B
B
Druet
P
P
Saoudi
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001792:Blood Platelets / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D004198:Disease Susceptibility / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D004676:Myelin Basic Protein / Q000276:immunology; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D053773:Transforming Growth Factor beta1
D000911:Antibodies, Monoclonal; D004676:Myelin Basic Protein; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens