LF 15-0195 inhibits the development of rat central nervous system autoimmunity by inducing long-lasting tolerance in autoreactive CD4 T cells.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-dependent autoimmune disease induced in susceptible animals by a single immunization with myelin basic protein (MBP). LF 15-0195 is a novel immunosuppressor that has been shown to have a potent immunosuppressive effect in several pathological manifestations. The purpose of this study was to investigate the effect of this drug on the induction and progression of established rat EAE and to dissect the mechanisms involved. We show that LF 15-0195 administration at the time of MBP immunization reduces the incidence and severity of EAE in Lewis rats. This drug also inhibits ongoing and passively induced EAE, indicating that LF 15-0195 affects already differentiated pathogenic lymphocytes. Compared with lymph node cells from untreated rats, lymphocytes from MBP-immunized rats treated with LF 15-0195 proliferated equally well in response to MBP in vitro, while their ability to produce effector cytokines and to transfer EAE into syngeneic recipients was significantly reduced. This phenomenon is stable and long-lasting. Indeed, neither IL-12 nor repeated stimulation with naive APC and MBP in vitro rendered MBP-specific CD4 T cells from protected rats encephalitogenic. In conclusion, LF 15-0195 treatment suppresses EAE by interfering with both the differentiation and effector functions of autoantigen-specific CD4 T cells.
Duplan
Valérie
V
Institut National de la Santé et de la Recherche Médicale, Unité 563, Institut Fédératif de Recherche 30, Hôpital Purpan, 31059 Toulouse Cedex, France.
Dutartre
Patrick
P
Mars
Lennart T
LT
Liblau
Roland S
RS
Druet
Philippe
P
Saoudi
Abdelhadi
A
D019264:Adoptive Transfer; D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D007116:Immunization, Passive; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D017634:Self Tolerance / Q000187:drug effects*; D012720:Severity of Illness Index
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D004676:Myelin Basic Protein