Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. III. A role for anergy/deletion.
Our previous work has shown that specific peripheral immune tolerance induced by the intravenous administration of ECDI-fixed, antigen-coupled syngeneic splenocytes is an extremely efficient method for prevention and treatment of chronic relapsing experimental autoimmune encephalomyelitis (R-EAE) in susceptible SJL/J mice. The current study examined the mechanisms by which unresponsiveness is induced in primed encephalitogenic T cells. The results indicate that the inhibition of MBP-specific T cells by the i.v. injection of MBP-coupled splenocytes is not due to the induction of antigen-specific regulatory T cells, but rather to the induction of anergy/deletion of the effector cells. This conclusion is supported by the findings that spleen or lymph node cells isolated from MBP-tolerant mice fail to inhibit the adoptive transfer of R-EAE in cotransfer assays, and that tolerance is not inhibited by prior thymectomy or prior treatment with cyclophosphamide or anti-CD8 monoclonal antibody. In contrast, we demonstrate that splenocytes from MBP-tolerized, asymptomatic mice have a significantly reduced ability to serially transfer R-EAE to naive secondary recipients following antigen re-activation in vitro, in the first several weeks following tolerization, but that the ability to serially transfer R-EAE returns to sham tolerant control levels within 1-2 months. We also demonstrate a significantly reduced precursor frequency of MBP-specific, IL-2-producing T cells in the MBP-tolerant within three days of treatment. Collectively, the data most closely support a model wherein inhibition of MBP-specific encephalitogenic CD4+ effector T cells by i.v. injected MBP-coupled splenocytes is due to the direct induction of anergy/deletion from which they can recover over time.
Tan
L J
LJ
Department of Microbiology-Immunology and the Interdepartmental immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Vanderlugt
C L
CL
McRae
B L
BL
Miller
S D
SD
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D002417:Cattle; D017635:Clonal Anergy / Q000276:immunology*; D017637:Clonal Deletion / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology*; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
D001324:Autoantigens; D004676:Myelin Basic Protein