Document 1147
 DOCN  M9591147
 TI    Functional evidence for epitope spreading in the relapsing pathology of
       experimental autoimmune encephalomyelitis.
 DT    9509
 AU    McRae BL; Vanderlugt CL; Dal Canto MC; Miller SD; Department of
       Microbiology-Immunology, Northwestern University; Medical School,
       Chicago, Illinois 60611, USA.
 SO    J Exp Med. 1995 Jul 1;182(1):75-85. Unique Identifier : AIDSLINE
       MED/95310867
 AB    The role of epitope spreading in the pathology of relapsing-remitting
       experimental autoimmune encephalomyelitis (R-EAE) was examined. Using
       peripherally induced immunologic tolerance as a probe to analyze the
       neuropathologic T cell repertoire, we show that the majority of the
       immunopathologic reactivity during the acute phase of R-EAE in SJL/J
       mice induced by active immunization with the intact proteolipid (PLP)
       molecule is directed at the PLP139-151 epitope and that responses to
       secondary encephalitogenic PLP epitopes may contribute to the later
       relapsing phases of disease. Intermolecular epitope spreading was
       demonstrated by showing the development of T cell responses to
       PLP139-151 after acute disease in mice in which R-EAE was initiated by
       the transfer of T cells specific for the non-cross-reactive MBP84-104
       determinant. Intramolecular epitope spreading was demonstrated by
       showing that endogenous host T cells specific for a secondary
       encephalitogenic PLP epitope (PLP178-191) are demonstrable by both
       splenic T cell proliferative and in vivo delayed-type hypersensitivity
       responses in mice in which acute central nervous system damage was
       initiated by T cells reactive with the immunodominant,
       non-cross-reactive PLP139-151 sequence. The PLP178-191-specific
       responses are activated as a result of and correlate with the degree of
       acute tissue damage, since they do not develop in mice tolerized to the
       initiating epitope before expression of acute disease. Most importantly,
       we show that the PLP178-191-specific responses are capable of mediating
       R-EAE upon adoptive secondary transfer to naive recipient mice.
       Furthermore, induction of tolerance to intact PLP (which inhibits
       responses to both the initiating PLP139-151 epitope and to the
       PLP178-191 epitope) after the acute disease episode is sufficient to
       prevent relapsing disease. These results strongly support a contributory
       role of T cell responses to epitopes released as a result of acute
       tissue damage to the immunopathogenesis of relapsing clinical episodes
       and have important implications for the design of antigen-specific
       immunotherapies for the treatment of chronic autoimmune disorders in
       humans.
 DE    Acute Disease  Amino Acid Sequence  Animal  Autoimmune
       Diseases/*IMMUNOLOGY/PATHOLOGY/THERAPY  Cross Reactions
       Desensitization, Immunologic  Encephalitogenic Basic Proteins/IMMUNOLOGY
       Encephalomyelitis, Allergic/*IMMUNOLOGY/PATHOLOGY/THERAPY  Female
       Immunodominant Epitopes/*IMMUNOLOGY  Immunotherapy, Adoptive  Lymphocyte
       Transformation  Mice  Mice, Inbred Strains  Molecular Sequence Data
       Myelin Proteins/*IMMUNOLOGY/TOXICITY/THERAPEUTIC USE  Peptide
       Fragments/*IMMUNOLOGY/TOXICITY/THERAPEUTIC USE  Recurrence  Support,
       U.S. Gov't, P.H.S.  Th1 Cells/*IMMUNOLOGY/TRANSPLANTATION  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).