Anti-tumor necrosis factor (anti-TNF) therapy abrogates autoimmune demyelination: New therapeutic implications for multiple sclerosis

Anti-tumor necrosis factor (anti-TNF) therapy abrogates autoimmune demyelination: New therapeutic implications for multiple sclerosis

113 ANTI-TUMOR NECROSIS FACTOR (ANTI-TNF) THERAPY ABROGATES AUTOIMMUNE DEMYELINATION: NEW THERAPEUTIC IMPLICATIONS FOR MULTIPLE SCLEROSIS Krzysztof Se...

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113 ANTI-TUMOR NECROSIS FACTOR (ANTI-TNF) THERAPY ABROGATES AUTOIMMUNE DEMYELINATION: NEW THERAPEUTIC IMPLICATIONS FOR MULTIPLE SCLEROSIS Krzysztof Seimai, Anne H. Cross and Cedric S. Raine Albert Einstein College of Medicine, Bronx, NY, USA The effect of a polyclonal antibody (Ab) against TNF, a cytoidne implicated in immune demyelination, was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein sensitized (MBP+) T iymphocytes, an animal model of the human disease, multiple sclerosis (MS). No mouse sensitized for EAE and then treated with anti-TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease in several experiments. CNS tissue from anti-TNF treated animals showed no pathologic changes. Controls demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti-TNF therapy was inhibitory to MBP÷ cells, preincubation of MBP+ T lymphocytes with anti-TNF in vitro prior to injection into recipient mice was performed and resulted in no diminution of their ability to transfer EAE. Also, spleen cells (SC) from anti-TNF treated mice were capable of serial transfer of EAE, similar to SC from controls. However, SC from anti-TNF treated mice produced no TNF upon stimulation with MBP or ConA. Therefore, anti-TNF .a_bCpFarently inhibits effectively the development of EAE by interfering with the effector, ~.ather than the induction, phase of the disease. Anti-TNF therapy may have important applications in the development of new therapeutic strategies for MS. (Supported by NMSS FG 795-A-1, JF 2042-A-2 and RG 1001-G-7. and NIH NS, 08952 and NS 11920).

EAMG AND ACETYLCHOLINE

RECEPTOR

ACETYLCHOLINE RECEPTOR AND E X P ~ A L AUTOIMMUNE MYASTHENIA GRAVIS: ACHIEVEMENTS/dqD PERSPECTI~,T,S S. Fuchs. Dept. of Chemical Immunology, The Weizmann Inst. of Science, Rehovot, Israel. It has been almost two ,~.ades since the original serendipitous observation of experimental autoimmunc myasthenia gravis (EAMG) in rabbits. This observation proved unequivocally the autoimmune nature of myas~henia gravis (MG) and established the nicotinic acethylcholine receptor (AChR) as the major target for autoimmune attack. Both AChR and EAMG have been studied extensively. A great deal of information on the structural, immunochemical and developmental properties of AChR has been accumulated. The receptor has been cloned and sequenced from several animal species and the application of molecular biology techniques allows the preparation of large amc,mts of various subunits and fragments of the receptor for immunological studies. Biologically active domains in the AChR molecule, such as the binding site, phosphorylation sites, ion channel domains and immunogenic regions have been defined. EAMG presents an ideal model for developing specific therapeutic means for eliminating the autoimmune response to AChR in MG. Several strategies for specific immunosuppression of EAMG will be discussed. These include: Modification of the receptor and of its T-cell epitopes, competing antibodies, antiidiotypes, anti-T cell receptor antibodies, anti-Ia antibodies and regulation of AChR synthesis. Future efforts towards specific therapy of EAMG and MG should take into consideration the heterogeneity of antibodies and the diversity of T-cell epitopes in these diseases.