title: Susceptibility to clinically manifest cyclosporine A (CsA)-induced autoimmune disease is associated with interferon-gamma (IFN-gamma)-producing CD45RC+RT6- T helper cells.
abstract: Lethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period, develop, upon withdrawal of CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmunity (CsA-AI). This T cell-mediated autoimmune disease is thymus-dependent; it is generally held that this disease is a consequence of aberrant T cell recovery brought about by CsA. In this study we determined mononuclear cell subsets phenotypically by tri-colour flow cytometry. A strong decrease in recent thymic emigrants (Thy1.1+, TCR alpha beta +) was observed as a consequence of CsA treatment, eventually resulting in decreased absolute peripheral T cell numbers. In these rats no altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4+ and CD8+ cells consisted predominantly of monocytes (CD4dim+, TCR alpha beta-) and natural killer cells (CD8+, TCR alpha beta-), respectively. LEW rats, x-irradiated, syngeneic bone marrow-reconstituted and treated with CsA, showed a marked and persistent, relative expansion of mature CD45RC+, RT6- Th cells. In contrast, Brown-Norway rats treated in a similar fashion, or LEW rats subjected to either CsA treatment or x-irradiation, did not show a comparable expansion of mature CD45RC+, RT6- Th cells, nor did these animals develop CsA-AI. The CD45RC+, RT6- Th cells produced IL-2, and moreover constituted the only Th subset producing IFN-gamma upon stimulation, and therefore were considered as Th1-like effector cells. These results are consistent with the view that a persistent preponderance of Th1 cells and not the mere presence of autoreactive cells determines whether or not clinically manifest CsA-AI will occur.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Limburg, Maastricht, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: Beijleveld
authors.forename: H
authors.initials: H
authors.lastname: Groen
authors.forename: C P
authors.initials: CP
authors.lastname: Broeren
authors.forename: F A
authors.initials: FA
authors.lastname: Klatter
authors.forename: J
authors.initials: J
authors.lastname: Kampinga
authors.forename: J G
authors.initials: JG
authors.lastname: Damoiseaux
authors.forename: P J
authors.initials: PJ
authors.lastname: van Breda Vriesman
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000209:etiology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002465:Cell Movement / Q000276:immunology; D016572:Cyclosporine / Q000633:toxicity*; D004198:Disease Susceptibility; D005260:Female; D006649:Histocompatibility Antigens / Q000032:analysis*; D007113:Immunity, Innate / Q000528:radiation effects; D007371:Interferon-gamma / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000032:analysis*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count / Q000528:radiation effects; D008562:Membrane Glycoproteins; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D006649:Histocompatibility Antigens; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D016572:Cyclosporine; D036002:ADP Ribose Transferases; C090163:Art2b protein, rat; D017493:Leukocyte Common Antigens