Laboratory of Immune Signal

1. Key Members

• Project leader - Tetsuji Naka
• Senior researcher - Minoru Fujimoto, Satoshi Serada
• Researcher - Kota Iwahori, Ayako Kim
• Technical assistant - Maiko Urase
• Graduate students (Graduate School of Medicine, Osaka University) - Tomoharu Ohkawara, Fumitaka Terabe, Tsuyoshi Takahashi, Yoshihito Souma, Yasuaki Miyazaki, Satoshi Hoki, Hiroshi Haruta, Shinya Matsuzaki, Takuhei Yokoyama, Yorihisa Kotobuki, Yong Mei
• Graduate students (Graduate School of Frontier Bioscience, Osaka University) - Tomohiro Ukita
• Collaborating Researcher (Graduate School of Frontier Bioscience, Osaka University) - Barry Ripley
• Collaborating Researcher (Graduate School of Health and Sports Science, Osaka University) - Teppei Nishikawa
• Secretary - Yukako Ito, Namiko Kawakami

2. Background and objectives

I. Characterization of novel immune regulatory proteins

The excess activation of immune system destroys self tissues and causes intractable diseases such as autoimmune diseases. To prevent such deregulation in immune systems, many kinds of inhibitory mechanisms are present in the body. We are investigating the novel molecules which are involved in the immune regulation. So far, we identified a unique molecule which is specifically expressed in the activated CD4 positive T cells and clarification of its function is on the way.

Figure1. A molecule (clone #88) is specifically expressed in the activated CD4 positive T cell (northern blotting analysis). We identified a novel membrane protein (clone #88) from mRNA library of CD4 positive T cells activated in the presence of an immunosuppressive cytokine, TGF-beta. This molecule is strongly expressed in the activated CD4 positive T cells, but not in the normal murine tissue including spleen and lymph node and various cell lines. We are generating gene-modified mouse of this molecule and investigating the role of this molecule in the immune regulation.

II. Target cell-specific delivery of SOCS molecules and application of its cancer treatment and adjuvant for vaccines.

Cytokines are intercellular messengers that are as essential to living animals like hormones. Abnormalities in cytokine signaling, however, may cause a variety of disorders such as autoimmune diseases, cancers and chronic inflammatory conditions. Therefore, the body has regulatory systems to prevent excessive signaling. For example, molecules named suppressor of cytokine signaling (SOCS) are critical regulators of cytokine signaling and also of innate immune signaling and insulin signals. It is also known that SOCS-deficient mice are highly susceptible to a number of disorders including autoimmune diseases and cancers. Our laboratory investigates the relationship between human diseases and the SOCS molecules, in order to develop SOCS-based therapies for autoimmune diseases, cancer, lifestyle diseases and infections.

II-1. Cancer cell-specific delivery of SOCS molecules and its application to cancer treatment

We and others cloned SOCS in 1997 as cytokine-inducible inhibitors of JAK family of kinases. Recently, excess activation of JAK/STAT pathway has been reported to be involved in the proliferation of malignant cancer cells such as hepatocellular carcinoma, breast cancer, prostate cancer and leukemia. Because SOCS molecules are inhibitors of JAK, SOCS molecules can be a promising therapy of these cancers.

Figure2. Cytokines are intercellular messengers that perform essential functions for the differentiation, proliferation and survival of cells. It is, however, known that excessive levels of cytokines or excessive cytokine signaling can cause cancer, autoimmune abnormalities and inflammatory diseases. Therefore, the body possesses control mechanisms to prevent excessive cytokine signaling. The suppressor of cytokine signaling (SOCS) molecules were isolated in 1997 as negative feedback inhibitors of cytokine signaling. Currently, eight proteins have been identified according to their characteristic structural features (one SH2 domain and an SOCS Box domain).

Figure3. SOCS family proteins use different molecular mechanisms to regulate cytokine signaling. SOCS-1 binds to a tyrosine kinase, JAK, and controls its functions. Cytokine-inducible SH2-containing protein (CIS) and SOCS-2 interact with activated (tyrosine-phosphorylated) receptors, and control cytokine signaling though the competitive inhibition of STAT molecules. SOCS-3 interacts with activated receptors and inhibits the function of JAK molecules to control cytokine signaling.

Figure4. Lines of evidence indicate that the abnormal expression of SOCS molecules or their genetic mutations are implicated in various diseases, including infectious disease, cancers and autoimmune diseases. We believe that controlling the expression and function of SOCS molecules will be useful to develop novel therapies for these diseases.

Figure5. Our research group tries to establish the delivery systems to introduce SOCS family genes or proteins into specific cells and develop novel SOCS-based therapies for cancer, autoimmune diseases and intractable infections.

The development of cancer cell-specific delivery system of SOCS molecules is currently on the way in our laboratory. By encapsulating SOCS genes expression vector into nano-particles labeled with cancer antigen-specific antibody, we will develop cancer cell-specific delivery of SOCS molecules in vivo. Introducing SOCS molecules specifically into cancer cells will terminate proliferation of cancer cells via inhibition of JAK, without affecting normal cells.

III. Proteomic analysis of disease-related proteins.

Establishment of treatment for malignant tumors (such as Lung Cancer, Gastrointestinal Cancer and Ovarian Cancer) and autoimmune disorders (such as Rheumatoid Arthritis) remains a crucial problem. The pathogenic mechanism of these diseases is still unclear and disease-specific therapy has not been developed yet. Protein analysis of clinical samples can provide valuable information (such as expression levels, cellular localization and posttranslational modifications) on disease-related proteins and will be helpful to elucidate pathogenic mechanism and therapeutic targets. Taking advantage of state-of-the-art proteomics technologies, and in collaboration with Osaka University Graduate School of Medicine (Departments of Allergy and Rheumatic Diseases, Respiratory Medicine, Thoracic Surgery, Gastrointestinal Surgery, Gastrointestinal Medicine, Obstetrics and Gynecology, Ophthalmology, Dermatology, Nephrology etc.), we try to identify new therapeutic targets and disease-related biomarkers by analyzing clinical samples with quantitative proteomic approaches.

Figure6. We apply proteomics technologies in profiling of disease-related proteins in intractable diseases such as cancers and autoimmune diseases. Our research group tries to identify new biomarkers and therapeutic targets for these diseases.

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