LF 15-0195 treatment protects against central nervous system autoimmunity by favoring the development of Foxp3-expressing regulatory CD4 T cells.
Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human demyelinating disease multiple sclerosis. Lewis (LEW) rats immunized with myelin-basic protein (MBP) develop EAE characterized by a single episode of paralysis, from which they recover spontaneously and become refractory to a second induction of disease. LF 15-0195 is a novel molecule that has potent immunosuppressive effects in several immune-mediated pathological manifestations, including EAE. In the present study, we show that a 30-day course of LF 15-0195 treatment not only prevents MBP-immunized LEW rats from developing EAE but also preserves their refractory phase to reinduction of disease. This effect is Ag driven since it requires priming by the autoantigen during the drug administration. In contrast to other immunosuppressive drugs, short-term treatment with this drug induces a persistent tolerance with no rebound of EAE up to 4 mo after treatment withdrawal. This beneficial effect of LF 15-0195 on EAE does not result from the deletion of MBP-specific Vbeta8.2 encephalitogenic T cells. In contrast, this drug favors the differentiation of MBP-specific CD4 T cells into Foxp3-expressing regulatory T cells that, upon adoptive transfer in syngeneic recipients, prevent the development of actively induced EAE. Finally, we demonstrate that the tolerance induced by LF 15-0195 treatment is not dependent on the presence of TGF-beta. Together, these data demonstrate that short-term treatment with LF 15-0195 prevents MBP-immunized LEW rats from EAE by favoring the development of Foxp-3-expressing regulatory CD4 T cells.
Duplan
Valérie
V
Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Fédératif de recherche 30, and Université Paul Sabatier, Hôpital Purpan, Toulouse, France.
Beriou
Gaëlle
G
Heslan
Jean-Marie
JM
Bruand
Corinne
C
Dutartre
Patrick
P
Mars
Lennart T
LT
Liblau
Roland S
RS
Cuturi
Maria-Cristina
MC
Saoudi
Abdelhadi
A
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology / Q000517:prevention & control; D004676:Myelin Basic Protein / Q000276:immunology; D009500:Neutralization Tests; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; D004247:DNA