Methylprednisolone induces reversible clinical and pathological remission and loss of lymphocyte reactivity to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis (MS). EAE, induced by immunisation with myelin-associated autoantigens, is characterised by an inflammatory infiltrate in the central nervous system (CNS) associated with axonal degeneration, demyelination and damage. We have recently shown in an experimental mouse model of autoimmune gastritis that methylprednisolone treatment induces a reversible remission of gastritis with regeneration of the gastric mucosa. Here, we examined the effect of oral methylprednisolone on the mouse EAE model of human MS induced by immunisation with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)). We examined the clinical scores, CNS pathology and lymphocyte reactivity to MOG(35-55) following treatment and withdrawal of the steroid. Methylprednisolone remitted the clinical signs of EAE and the inflammatory infiltrate in the CNS, accompanied by loss of lymphocyte reactivity to MOG(35-55) peptide. Methylprednisolone withdrawal initiated relapse of the clinical features, a return of the CNS inflammatory infiltrate and lymphocyte reactivity to MOG(35-55) peptide. This is the first study to show that methylprednisolone induced a reversible remission in the clinical and pathological features of EAE in mice accompanied by loss of lymphocyte reactivity to the encephalitogen. This model will be useful for studies directed at a better understanding of mechanisms associated with steroid-induced disease remission, relapse and remyelination and also as an essential adjunct to an overall curative strategy.

Liposomal Encapsulation of Glucocorticoids Alters Their Mode of Action in the Treatment of Experimental Autoimmune Encephalomyelitis

“…Our data demonstrate that GCs fall into two categories concerning their efficacy in the treatment of EAE, with the two fluorinated compounds Dex and triamcinolone being superior to the nonhalogenated GC prednisolone and MP. This finding is in contrast to a report showing that MP completely reversed EAE in the C57BL/6 model, where the dosage, delivery route, and application frequency differed significantly from our protocol (32).…”

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

“…Animals were monitored daily for 6 weeks and neurological impairment scored on an arbitrary clinical score: 0, no clinical sign; 1, limp tail; 2, limp tail and hind limb weakness; 3, complete hind limb paresis; 4, complete hind and fore limb paresis; 5, moribund or death. 6,52 As recommended by the Animal Ethics Committee, mice were euthanised when they reached a clinical score of 3. For re-immunization experiments, mice that remained disease free for 6 weeks during the clinical observation period were given an additional 8 week of rest before subsequent re-immunized.…”

Gene Therapy Delivery of Myelin Oligodendrocyte Glycoprotein (MOG) via Hematopoietic Stem Cell Transfer Induces MOG-Specific B Cell Deletion

“…In mice, this protocol has been shown to enhance negative selection of developing self-reactive MOG-specific CD4 + T cells in the thymus (7). Combined with a course of prednisolone to initially promote remission (28), the transfer of transduced BM can also be used to cure existing EAE and prevent relapses, even following secondary immune challenges (7). However, these studies have focused only on MOG-reactive CD4 + T cells, and there is no information on whether this procedure will also affect the B cell compartment and tolerance toward MOG-specific B cells.…”