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The pathogenesis of multiple sclerosis (MS) remains to be elucidated and there is no curative therapy against MS, though we have several disease modifying drugs. In this symposium. I introduce several new strategies against development of autoimmune processes and axonal degeneration in MS. Several mechanisms regulate immune system not to attack self components. One of the most potent regulatory cells is CD4 + CD25 + FoxP + regulatory T cells (Treg), which suppress development of both T helper 1 and 2. Thus, to increase the number and function of Treg is an approach to suppress autoimmune diseases. We have found recently that midkine suppresses the development of Treg. and that suppression of midkine by RNA aptamer alleviates symptoms of experimental autoimmune encephalomyetitis, an animal model of MS. by expanding Treg. Another important strategy against MS is to suppress axonal degeneration which reportedly occurs from an early stage of MS. We have found that the most toxic agent from activated macrophages and microglia is glutamate that was produced by glutaminase and released through gap-junction. Thus, inhibitor for glutaminase and gap-junction may be other candidates to treat MS. Interferon-beta also effectively suppress glutamate production by these cells and subsequently suppress development of axonal degeneration.

We have established the assay conditions of midkine (MK) measurement, the reference intervals and evaluation for clinical significance of blood MK measurement. MK is a kind of cytokines and basic protein which is a heparin-binding growth factor of various cells. The increase of MK expression suggests a prognostic value in early stage on cancers or inflammation. But significant problems in the MK measurement are alterations resulting from standing time and temperature instability after blood collection. Assay of MK was performed with solid phase human MK immunoassay recently developed sensitive enzyme linked immunosorbent method. The assay condition of MK was required to be separated immediately after blood sampling within 24 hrs at 4 degrees C or within 2 hrs at room temperature-standing. Plasma sample obtained with EDTA-2Na or citric acid-Na, and serum obtained from plain tube container showed good results. Linearity was obtained up to 1500 pg/ml and repeatability and reproducibility were within 10% as CV%. The recovery of MK was 101.1+/-3.8% with 10 specimens ranged 97-105%. Addition of interfering substances showed no effect on assay results when hemoglobin, EDTA-Na, citrate and turbidity check, but conjugated bilirubin (over 0.68 mmol/l) and gave negative errors within 10% in the assay results and heparin gave negative errors. The reference interval was 550 +/- 160 pg/ml in healthy individuals serum.

Midkine is a heparin-binding growth factor, implicated in various biological phenomena such as neuronal survival and differentiation, tissue remodeling and carcinogenesis. Together with pleiotrophin, midkine constitutes a family that is distinct from other heparin-binding growth factors. In this review, I will briefly describe biochemical and biological characteristics of midkine and then focus on its biological significance in cancer. The most intriguing feature of midkine in cancer is its augmented expression in advanced tumors at very high frequency in non-tissue specific manner. In addition, its high expression is also detected in precancerous lesions. Midkine exerts carcinogenesis-related activities, including transforming, anti-apoptotic, angiogenic and fibrinolytic ones. These data provide a possibility of clinical application of midkine. Serum midkine level can be a useful tumor marker. Gene therapy using its promoter region and therapeutic strategy choosing midkine as a molecular target are worth challenging.

We studied the protective effects of midkine, a growth factor produced by a retinoic acid responsive gene, on constant light-induced retinal damage in albino BALB/C adult mice. Two days before exposure to constant light, midkine was injected into the vitreous of the left eye and a phosphate buffer saline into the right eye (control eyes). After 7 days of constant light, control eyes exhibited shortening of the photoreceptor outer segments and decreased thickness of the outer nuclear layer, whereas in midkine-treated eyes photoreceptor cells were virtually intact. Although midkine-treated eyes also showed photoreceptor damage after longer light exposure of up to 21 days, the damage was significantly less than in control eyes. Measurement of the thickness of the outer nuclear layer showed the protective effect of intravitreous midkine on the constant light-induced retinal damage. These findings suggest that midkine is a potential agent for the prevention of photoreceptor degeneration.

Midkine (MK) is a novel heparin-binding growth factor whose expression is regulated by retinoic acid. Midkine is structurally unrelated to other growth factors, and together with pleiotrophin (PTN) subsequently cloned forms a new family of growth factors. Midkine enhances neurite outgrowth and survival of several embryonic neurons. Midkine mRNA is strongly expressed in the nervous system during the midgestation period, while the normal adult brain scarcely expresses it. Immunohistochemical studies revealed midkine localization beside radial glial processes along which neurons migrate. Upon experimental brain infarction in the rat, midkine expression in the ischemic region begins as early as 1 day after the operation. Senile plaques of patients with Alzheimer's disease invariability express midkine. These findings indicate that midkine plays significant roles both in the formation and repair of the central nervous system and processes leading to its diseases.