Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

These findings suggest that MS phenotypes are drastically altered by environmental factors, such as latitude and "Westernization."

Anti-CD3 monoclonal antibody (mAb) has been shown to induce tolerance and to be an effective treatment for diabetes both in animal models and in human trials. We have shown that anti-CD3 mAb given orally is biologically active in the gut and suppresses experimental autoimmune encephalitis by the induction of a regulatory T-cell that expresses latency-associated peptide (LAP) on its surface. In the present study, we investigated the effect of oral anti-CD3 mAb on the prevention of autoimmune diabetes in AKR mice in which the low-dose streptozocin (STZ) model induces autoimmunity to the ␤-cells of the islets. We found that oral anti-CD3 mAb given at doses of 50 and 250 g/feeding suppressed the incidence of diabetes in this model with the best effects seen at the 50 g/dose. Associated with suppression, we observed decreased cell prolif- I mmunological tolerance is mediated by a number of mechanisms, and it is generally believed that autoimmune processes such as those that occur in type 1 diabetes are in some way related to defects in immunological tolerance (1). One approach for the treatment of autoimmunity has been the parenteral administration of anti-CD3 monoclonal antibody (mAb), which is efficacious in animal models of autoimmunity including autoimmune diabetes (2-7) and experimental allergic encephalomyelitis (EAE) (8,9) and in human trials of type 1 diabetes (10 -12). Intravenous (IV) anti-CD3 mAb is an approved therapy for transplant rejection in humans (13). We have been interested in immune therapy of autoimmune diseases by mucosal administration of autoantigens designed to induce regulatory T-cells (14,15). We have recently found that oral anti-CD3 mAb is biologically active in the gut and induces a CD4 ϩ CD25 Ϫ latency-associated peptide (LAP) ϩ regulatory T-cell that suppresses EAE in a transforming growth factor (TGF)-␤-dependent fashion (16). LAP is the NH 2 -terminal domain of the TGF-␤ precursor peptide; it remains noncovalently associated with TGF-␤ peptide after cleavage and forms the latent TGF-␤ complex. We previously identified CD4 ϩ CD25 Ϫ LAP ϩ T-cells that suppress colitis by a TGF-␤-dependent mechanism (17).Given this finding, we investigated the effect of oral anti-CD3 mAb in AKR mice on the prevention of autoimmune diabetes using the low-dose streptozocin (STZ) model, which induces autoimmunity to ␤-cells (18). Diabetes in the STZ model can be prevented by administration of anti-T-cell monoclonal antibodies, and diabetes can be adoptively transferred with splenocytes from diabetic animals (19). This model is useful for the testing of novel immunotherapeutic interventions because hyperglycemia and insulitis can be easily induced in a relatively short period of time in a high percentage of animals. Furthermore, treatment can be given before irreversible tissue damage and before T-cells have become sensitized to islet antigens. It was previously shown by Herold et al. (2) that IV anti-CD3 mAb is effective in the STZ model. Given our results in the EAE model, we investigated the effect of o...