title: Glucocorticosteroids modulate antigen-induced T cell apoptosis in experimental autoimmune neuritis and cause T cell proliferation in situ.
abstract: Treatment of experimental autoimmune disorders of the nervous system with high doses of glucocorticosteroids (GC) or with administration of the specific antigen is effective and associated with marked T cell apoptosis in situ. Here we investigated in adoptive transfer-experimental autoimmune neuritis (AT-EAN) of the Lewis rat whether induction of T cell apoptosis resulting from T cell activation by antigen therapy can be further augmented by glucocorticosteroids (GC). AT-EAN was induced by intravenous injection of P2-specific T cell blasts. At the maximum of disease two pulses of the antigen recombinant human P2 (rhP2) were given within 12 h. Methylprednisolone was administered simultaneously or 2 h after the antigen and animals were killed 6 h after the second antigen injection. Using an in situ tailing technique followed by immunocytochemical analysis, the presence of DNA fragmentation in T lymphocytes was confirmed. The bromodeoxyuridine (BrdU) technique was employed to detect in situ proliferating cells. T cell apoptosis in sciatic nerve was enhanced after monotherapy with either antigen or GC compared to the control group receiving an irrelevant myelin protein, recombinant human P0. In combination therapy, a synergistic effect on T cell apoptosis in sciatic nerve was obtained when methylprednisolone was injected sequentially, 2 h after rhP2 protein. BrdU incorporation in the sciatic nerve as well as in the spleen, a major lymphoid organ, was significantly enhanced in animals treated with antigen followed by GC 2 h later as compared to rats receiving rhP2 only, speaking for T cell proliferation in situ associated with T cells undergoing apoptosis. Our findings underscore that different proapoptotic stimuli may act synergistically, depending on the timing of the second treatment. In this scenario even local T cell proliferation in the inflamed nervous system occurs. These results support the paradigm of antigen presentation in the nervous system.
authors.affiliation: Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians Universität, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Weishaupt
authors.forename: L M
authors.initials: LM
authors.lastname: Schönrock
authors.forename: M
authors.initials: M
authors.lastname: Stienekemeier
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: R
authors.initials: R
authors.lastname: Gold
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004338:Drug Combinations; D006801:Humans; D007700:Kinetics; D018996:Myelin P2 Protein / Q000494:pharmacology*; D009444:Neuritis, Autoimmune, Experimental / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D011994:Recombinant Proteins; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology*
chemical_list: D000305:Adrenal Cortex Hormones; D004338:Drug Combinations; D018996:Myelin P2 Protein; D011994:Recombinant Proteins