Modification of Acute Experimental Autoimmune Encephalomyelitis in the Lewis Rat by Oral Administration of Type 1 Interferons

Abstract

The effect of orally administered type 1 interferons on the severity of acute experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease, was examined by inoculation of Lewis rats with guinea pig myelin basic protein (GPMBP) and complete Freund's adjuvant. Rats were fed either rat species-specific or human recombinant type 1 interferon (IFN) or mock IFN daily for 7 days preceding immunization and for 21 days thereafter. There was a significant decrease in the clinical score and inflammatory foci in animals fed 5000 units IFN compared with mock-treated animals. There was a significant decrease in clinical score and number of inflammatory foci in spinal cord in animals fed orally 5000 units human recombinant IFN-alpha PO compared with SC 5000 units recombinant human IFN-alpha. Oral administration of type 1 interferon, as opposed to subcutaneous administration, inhibited the secretion of IFN-gamma from ConA-activated draining popliteal lymph node cells compared with mock-fed animals. These experiments demonstrate that acute EAE is more effectively inhibited by equivalent amounts of orally in contrast to parenterally administered IFN-alpha. These results suggest that type 1 IFNs are active by the oral route and have significant clinical and histologic effects in acute autoimmune disease.

Oral administration of interferon-β suppresses experimental autoimmune uveoretinitis

“…Both oral and intraperitoneal administration of IFN can decrease peripheral white blood cell counts, although circulating antibody to IFN can block this effect only with intraperitoneal administration but not with oral administration [16]. Moreover, it has been shown that low-dose IFN, while ineffective if given parenterally, is able to suppress disease in the EAE model when given orally [9]. Such potential efficacy, combined with the obvious benefit of ease of administration, has made oral IFN therapy a viable alternative to injected therapy.…”

“…Rats were treated daily with various doses (10 2 , 10 3 , 10 4 or 10 5 IU) of mouse recombinant IFN-β starting 7 days before immunization through the day of killing. This protocol was similar to that previously described for EAE [9]. Because IFN is absorbed best from the oropharyngeal cavity [26], the IFN-β was administered by direct application to the oropharyngeal mucosa using a micropipette.…”

“…Oral type I IFNs have been reported to reduce the severity of inflammation in several animal models of autoimmune disease such as experimental autoimmune encephalomyelitis (EAE) in mice [7,8] and rats [9], non-obese diabetic (NOD) mice [11] and collagen-induced arthritis [36]. Oral administration of type I IFNs have also been shown to be effective in patients with multiple sclerosis [10], rheumatoid arthritis, insulin-dependent diabetes mellitus [6] and Sjög-ren's syndrome [31].…”

Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis

“…These problems are, in part, due to the lack of diversity in EAE models using inbred strains of mice, various misconceptions about our understanding of the pathophysiology of EAE from knockout mice, the relatively small numbers of animals used in EAE test systems, and the short time interval for testing even 'chronic' therapies in EAE, in which experiments might need to run for years, not weeks or months, to model chronic human therapy. Despite its pitfalls, EAE has been a useful model for predicting success with clinical trials in multiple sclerosis (MS).Currently, there are several approved therapies for MS, including glatiramer acetate [1-8], mitoxantrone [9-11], various b interferons (IFNs) [12,13] and natalizumab [14][15][16][17], which has been withdrawn currently from the market by its manufacturers. Glatiramer acetate is one of the hallmarks of current therapy and was developed based on its ability to modulate EAE [1][2][3][4][5][6][7][8].…”

“…Currently, there are several approved therapies for MS, including glatiramer acetate [1][2][3][4][5][6][7][8], mitoxantrone [9][10][11], various b interferons (IFNs) [12,13] and natalizumab [14][15][16][17], which has been withdrawn currently from the market by its manufacturers. Glatiramer acetate is one of the hallmarks of current therapy and was developed based on its ability to modulate EAE [1][2][3][4][5][6][7][8].…”