Gene therapy in autoimmune, demyelinating disease of the central nervous system.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies. Although neuroprotection strategies are relatively unexplored in MS, systemic delivery of anti-inflammatory agents to people with MS has so far been relatively disappointing. This is most probably because of the limited capacity of these molecules to enter the target tissue, because of exclusion by the blood-brain barrier. The complex natural history of MS also means that any therapeutic agents will have to be administered long-term. Gene therapy offers the possibility of site-directed, long-term expression, and is currently being preclinically investigated in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. While some immune effects may be targeted in the periphery using DNA vaccination, strategies both viral and nonviral are being developed to target agents into the CNS either via direct delivery or using the trafficking properties of cell-carrier systems. Targeting of leucocyte activation, cytokines and nerve growth factors have shown some promising benefit in animal EAE systems, the challenge will be their application in clinical use.

Experimental autoimmune uveoretinitis in mice (Biozzi ABH and NOD) expressing the autoimmune-associated H-2A(g7) molecule: identification of a uveitogenic epitope.

To determine whether Biozzi ABH (H-2A(g7)) mice were susceptible to chronic experimental autoimmune uveoretinitis (EAU). Biozzi ABH were immunized with the two retinal antigens, interphotoreceptor retinoid binding protein (IRBP) and soluble antigen (S-Ag). Biozzi ABH mice were found to be susceptible to EAU induction with native bovine IRBP. Recombinant protein domains were used to identify IRBP domain 2 (EcR2) as the uveitogenic domain. Histopathological examination indicated that EcR2-induced disease was of a chronic, non-destructive nature in the Biozzi ABH. Using synthetic overlapping peptides corresponding to EcR2, a uveitogenic and immunogenic epitope was identified corresponding to human IRBP511-530. Non-obese diabetic (NOD) mice share the same MHC class II (H-2A(g7)) molecule as the Biozzi ABH, and were also found to be susceptible to EAU induction with EcR2. This study has identified a novel mouse model of EAU, whereby disease is of a chronic, non-destructive nature, which has potential to be used in immune manipulation and neuroprotection studies.

Interphotoreceptor retinoid binding protein peptide-induced uveitis in B10.RIII mice: characterization of disease parameters and immunomodulation.

Experimental autoimmune uveoretinitis (EAU) can be induced in the B10.RIII mice following immunization with bovine interphotoreceptor retinoid binding protein (IRBP) and human IRBP(161--180)peptide. This study examines the value of the human IRBP(161--180)peptide model in the B10.RIII mice, as a suitable model of EAU in order to examine immunotherapies. Having established a reliable and consistent immunization protocol of 25 micro g peptide and no PTX, the time course of histopathology was performed, which graded both cellular and structural scores individually. Disease was typically of an acute nature, characterized by rapid onset of a massive inflammatory response, resulting in extensive damage to the rod outer segments (ROS) and neuronal layers. Treatment with potent immunosuppressive agents, CD4-specific monoclonal antibodies resulted in the inhibition of disease and a reduction in disease incidence. Treatment with p55-tumor necrosis factor receptor-Ig (p55-TNFR-Ig) fusion protein reduced structural damage to the retina despite a high level of cellular infiltration in the eye, suggesting that target organ damage in an acute model of EAU can be modulated.