FUNCTIONAL EVIDENCE FOR EPITOPE SPREADING IN THE RELAPSING PATHOLOGY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

被引:438
作者
MCRAE, BL
VANDERLUGT, CL
DALCANTO, MC
MILLER, SD
机构
[1] NORTHWESTERN UNIV,SCH MED,DEPT MICROBIOL IMMUNOL,CHICAGO,IL 60611
[2] NORTHWESTERN UNIV,SCH MED,DEPT PATHOL,CHICAGO,IL 60611
关键词
D O I
10.1084/jem.182.1.75
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:75 / 85
页数:11
相关论文
共 48 条
[1]   T-CELLS RESPONSIVE TO MYELIN BASIC-PROTEIN IN PATIENTS WITH MULTIPLE-SCLEROSIS [J].
ALLEGRETTA, M ;
NICKLAS, JA ;
SRIRAM, S ;
ALBERTINI, RJ .
SCIENCE, 1990, 247 (4943) :718-721
[2]  
Alvord E. C. J., 1984, EXPT ALLERGIC ENCEPH
[3]  
BROWN AM, 1981, LAB INVEST, V45, P278
[4]   UP-REGULATION AND COEXPRESSION OF ADHESION MOLECULES CORRELATE WITH RELAPSING AUTOIMMUNE DEMYELINATION IN THE CENTRAL-NERVOUS-SYSTEM [J].
CANNELLA, B ;
CROSS, AH ;
RAINE, CS .
JOURNAL OF EXPERIMENTAL MEDICINE, 1990, 172 (05) :1521-1524
[5]   DEVELOPMENT OF REACTIVITY TO NEW MYELIN ANTIGENS DURING CHRONIC RELAPSING AUTOIMMUNE DEMYELINATION [J].
CROSS, AH ;
TUOHY, VK ;
RAINE, CS .
CELLULAR IMMUNOLOGY, 1993, 146 (02) :261-269
[6]  
DALCANTO MC, 1975, LAB INVEST, V33, P626
[7]   ROLE OF INTERMOLECULAR INTRASTRUCTURAL B-CELL AND T-CELL DETERMINANTS IN THE DIVERSIFICATION OF AUTOANTIBODIES TO RIBONUCLEOPROTEIN-PARTICLES [J].
FATENEJAD, S ;
MAMULA, MJ ;
CRAFT, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (24) :12010-12014
[8]  
FRITZ RB, 1983, J IMMUNOL, V130, P1024
[9]  
GREER JM, 1992, J IMMUNOL, V149, P783
[10]   SPONTANEOUS LOSS OF T-CELL TOLERANCE TO GLUTAMIC-ACID DECARBOXYLASE IN MURINE INSULIN-DEPENDENT DIABETES [J].
KAUFMAN, DL ;
CLARESALZLER, M ;
TIAN, JD ;
FORSTHUBER, T ;
TING, GSP ;
ROBINSON, P ;
ATKINSON, MA ;
SERCARZ, EE ;
TOBIN, AJ ;
LEHMANN, PV .
NATURE, 1993, 366 (6450) :69-72