Mouse models autoimmunity

In a mouse model for autoimmune non-obese diabetes (NOD), the full-blown diabetes could be reversed to normoglycaemia by treatment with CD3 antibodies. In these diabetes- tolerant mice, the proportions of CD4+ CD25+ regulatory T cells were increased. Moreover, the CD4+ CD25+ regulatory T cells of the tolerant mice produced high levels of... 

Similarly, under certain disease conditions, altered NA innervation and/or AR signaling capacity impairs sympathetic communication with cells of the immune system, influencing disease progression. Altered catecholamine communication with the immune system is evident in autoimmune diseases such as arthritis and multiple sclerosis [5-7] and in infectious diseases, such as leprosy and a mouse model of acquired immunodeficiency syndrome [15, 43, 44], The impact of altered NA innervation of... 

In the next phase of the study, transcripts of up-regulated genes granulocyte colony-stimulating factor (G-CSF) and IgG were introduced into a mouse model corranonly used to test potential therapies for experimental autoimmune encephalomyelitis (EAE). Erom microarray analysis, G-CSF was found to be up-regulated in acute MS but not in the chronic state of the disease. Subcutaneous injection of G-CSF prior to induction of EAE prevented onset of the disease in mice. The reversal of EAE by G-CSE has also been described (see Eock, 2002, Reference 40). 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

Naked pDNA delivery of cytokines has also been evaluated in a number of mouse models of autoimmune disease. Naked pDNA delivery of TGF/3 to a murine model of systemic lupus erythematosus (SLE) led to lower serum IgG levels, decreased glomerulonephritis and increased survival (Raz et al., 1995). The pDNA (100 gg) was injected i.m. at 6, 10, 14, 18 and 22 weeks. Administration of IL-2 encoding pDNA had the opposite effect, resulting in increased semm IgG, increased glomerulonephritis, and decreased survival, demonstrating that a disease course could be significantly modulated by naked pDNA therapy. The pDNA (100 gg) was injected once in every two weeks for a total of five injections. Circulating semm levels of either IL-2 or TGF 0 w ere detected up to two weeks after the final pDNA injection into the muscle. 

Models of autoimmune diabetes in nonobese diabetic mice (NOD) mice, insulin-dependent diabetes, and experimental allergic encephalyomyelitis (EAE) were also used to evaluate naked pDNA therapy. In the latter models, a predominant Thl cytokine response is thought to play a role in disease symptoms and etiology. Treatment of these mouse models with a TH2 type cytokine, such as IL-10 or IL-4, has been found to shift the immune response and lessen the severity of disease. Therefore, the efficacy of pDNA delivery of a Th2 cytokine was explored in these specific models. 

Therapeutic monoclonal antibodies are widely recognized to be a most promising means to treat an increasing number of human diseases, including cancers and autoimmunity. To a large extent, the efficacy of monoclonal antibody treatment is because IgG antibodies have greatly extended persistence in vivo. However, conventional rodent models do not mirror human antibody pharmacokinetics. The key molecule responsible for the extended persistence antibodies is the major histocompatibility complex class I family Fc receptor, FcRn. We describe human FcRn transgenic mouse models and how they can be exploited productively for the preclinical pharmacokinetic evaluation of therapeutic antibodies. 

Petkova, S. B., Akilesh, S., Sproule, T. J., Christianson, G. J., A1 Khabbaz, H., Brown, A. C., et al. (2006) Enhanced half-life of genetically engineered human IgGl antibodies in a humanized FcRn mouse model potential application in Immorally mediated autoimmune disease. Int Immunol 18,1759-1769. 

The development of type 1 diabetes (T1D) in both humans and the NOD mouse model is due to the aberrant autoimmune... 

Comparison of islet allograft destruction and recurrent autoimmunity in NOD mouse models... 

Nagy A, Nagashima H, Cha S, Oxford GE, Zelles T, Peck A, Humphreys-Beher MG. Reduced oral wound healing in the NOD mouse model for type 1 autoimmune diabetes and its reversal by epidermal growth factor supplementation. Diabetes 2001 50 2100-2104. 

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