Name of Division: Pathology and Immunology

Staff

General information

　　　The Department of Pathology and Immunology is responsible for the education of "pathology" in general, to undergraduate students of the medical school of this university through lectures and practice together with the Department of Human Pathology. For post-graduate students of medical background and research workers for specialty of pathology, we are taking care of their exercise in clinicopathological training course to obtain the license of specialized Pathology Board. They are studying about biopsy, surgical and autopsy materials in the university hospital. As the researches for the department staffs and post-graduate students, we investigate dynamics of bio-defense system under infectious/stressed conditions as well as under influence of aging effect using pathological, immunological and molecular biological techniques. We are also engaged in clinicopathological research works using biopsy and surgical materials of the university hospital in cooperation with clinicians and researchers from other department/institute.

Education

　　Undergraduate Course

　We are engaged in the programs for pathology-"general remarks", pathology-"itemized details", pathology-"practice of each subjects", generalized exercise for diagnostics, bed-side learning (BSL) in the university hospital and clinicopathological exercise (CPE). These programs are performed for 4 years from the 3rd grade to 6th grade of the medical school program. Staffs from our department, the Department of Human Pathology and pathology-associated departments of Institute of Medical Sciences, Allied Health Sciences and School of Dentistry are taking charge of these programs. In pathology-"practice" programs, case-oriented exercise is performed. Students are divided into about 10 groups (7 to 8 students per one group) and each group takes charge of one case and studies about various informations from the clinical features to the pathological findings and outcomes. In CPE programs, several students (by turns) study about one case clinically as well as pathologically to present and introduce the results to all the other students. We expect that students would understand well about the diseases through studies with case-oriented experiences.

　　Graduate Course

　For post-graduate students of medical background, training of human pathology is expected to obtain the license of specialized Pathology Board. The Japanese association of pathologists recommends more than 5 years of experience to apply the license. Training course includes studies of anatomic pathology, autopsy pathology, surgical pathology, cytopathology, and correspondence for clinicopathological conference/surgical conferences with clinical departments of this university, and studies in other hospitals. We are inviting post-graduate students of non-medical background as well as medical background. To get the degree of medical doctor, research works should be completed and the paper should be published in the scientific journal. We prepare various and ultramodern methods/theme to satisfy each student's interest in the scientific research field. Usually, post-graduate students can finish doctor-course and obtain the degree within 4 years.

　

Research Subjects

　　　・Clinocopathological studies

　　 We are investigating various aspects of various diseases using biopsy, surgical and autopsy materials. Research works are performed to establish new entities of diseases, new technologies for diagnosis and new strategies for therapies. In addition to the usual histopathological examination, immunohistochemical, electron microscopic, and molecular pathological methods were used to progress the research. If necessary, any staffs/post-graduate students are welcome to use the clinical materials of the university hospital.

　　　・Experimental studies

　　　　 To examine the significance and property of hypothesis that have been made up through clinical/pathological experiences or clinicopathological researches, one can imagine and plan the experimental design using various tools for experimental pathology. We prepare various methodologies and use experimental animal models, as well as cultured cells for this object.

　

Introductions to each study

　1) General study for mechanisms of development of immune system and break down of the system with aging: Functions of immune systems develop rapidly after birth and peaked at the puberty, but deteriorated by aging thereafter. As the result, aged people who are more than 70 years old becomes prone to infectious diseases due to hypo-function of the immune system. To investigate the molecular mechanisms of age-changes of immune functions, we analyze the influences of ageing effect on the thymus, T lymphocytes and neuroendocrine systems.

　2) Signal transduction systems of T cells and their age change: Antigen stimulation of T cells begins at the antigen receptor (TCR) and transfers the signal through cascade of signal transduction system. Cellular proliferation as well as protein synthesis would be induced after the signal reaches to the nucleus. One of the causes for hypo-function of T cells in the elderly would be the abnormality in signal transduction systems that lie down-stream of the TCR. We have clarified that the abnormality exists in pathways including tyrosine kinases, phospholipase C and second messengers.

　3) T cell differentiation in the thymus -- analysis for molecular mechanisms of thymic microenvironment: Mechanisms of negative/positive selections of T cells in thymic microenvironment have been well documented recently. However, the initial signal that induces differentiation of bone marrow-derived T cell progenitors to mature T cells is still uncertain. We investigate the thymic microenvironment using gene-manipulation technology and analyze the character of the initial ligand that induces the proliferation/differentiation of T cells in the thymus.

　4) Molecular mechanisms of cross-talks in neuro-endocrine-immune system: Neurons in the brain/peripheral nerves are known to interact each other (cross-talk) via common mediators. We analyze the expression of cytokine receptors on nerve cells from various portions of the brain under conditions of stresses and /or infections.

　5) Analysis of molecular mechanisms for pathogenesis of retrovirus-induced disease and establishment of gene therapy model: Various factors are considered for controlling the susceptibility to retrovirus-induced diseases. We have clarified the relation between host T cell functions and tumor induction mechanisms by Friend leukemia virus. To further investigate the host-virus relation, changes of signal transduction systems and T cell functions after retroviral infection are analyzed. In addition, gene therapy model using receptor interference effect by envelope protein of the virus has been established and analyzed.

　6) Molecular pathological approach to mechanisms of myelodysplastic syndromes (MDS) development: MDS is a hematological malignancy mainly affecting the elderly people. We found that hematopoietic cells of the bone marrow exhibited marked apoptosis in MDS patients. The frequent apoptosis of bone marrow cells would be the cause of peripheral cytopenias usually seen in MDS patients. Molecular mechanisms regulating apoptosis in MDS are investigated from aspects of the hematopoietic cells themselves and the surrounding stromal cells.

　7) Transcriptional factors inducing T cell differentiation: We cloned the cDNA of novel transcription factor from the cortical epithelial cells of the thymus. This factor is essential for inducing T cell differentiation Now we are analyzing the function of the gene using in situ hybridization technique (determination of expression site) and by producing knockout mice.

　8) ODF (OPGL, RANKL, TRANCE), a factor for regulating bone metabolism and T cell differentiation: Recently, osteoblast-derived factor, ODF, which usually induces osteoclast in bone tissue has been found to induce T cell differentiation. We found several isoforms of ODF and now analyze their functions for regulating transcription and physiological functions.

　9) Molecular pathological examination of proliferation/progression of cancer: Molecular pathological analysis of tumor proliferation/progression is performed using human cancer materials from various organs mainly from GI tract.

　

Publications

　　1 Utsuyama M, Seidler H, Kitagawa M and Hirokawa K. Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice. Mech. Ageing Dev.122:341-352, 2001.

　　2 Ikeda T, Kasai M, Utsuyama M and Hirokawa K. Determination of 3 isoforms of RANKL and their differential expression in bone and thymus. Endocrinol. 142:1419-1426, 2001.

　　3 Asanuma H, Hirokawa K, Utsuyama M, Suzuki Y, Aizawa C, Kurata T, Sata T and Tamura S. Immune responses and protection in different strains of aged mice immunized intranasally with an adjuvant-combined influenza vaccine. Vaccine 19:3981-9, 2001.

　　4 Hirokawa K, Utsuyama M and Kobayashi S. Hypothalamic control of thymic function. Cell. Mol. Biol. 47:97-102, 2001.

　　5 Shiraishi J, Utsuyama M, Akashi T, Nemoto T, Ohashi K, Akamatsu H, Sunamori M, Kitagawa M and Hirokawa K. Immunohistological analysis of thymoma by molecules differentially expressed in thymic cortex and medulla, and its application for differential diagnosis of thymoma from esophageal and lung cancer. Pathol. Res. Prac. 197:611-619, 2001.

　　6 Ikeda T, Utsuyama M and Hirokawa K. Expression profiles of RANKL, RANK and OPGmRNA in aged and ovariectomized rat bones. J.Bone Miner.Res.16:1416-1425, 2001.

　　7 Nonomura Y, Kohsaka H, Nasu K, Terada Y, Ikeda M, Miyasaka N. Related Articles Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21(Cip1) gene into the joints. Int Immunol. 13(6):723-31, 2001.

　　8 Pawelec G, Tamas F and Hirokawa K. Altered T cell signalling in ageing. Aging Research Review Mech. Ageing Dev. 122:1613-1637, 2001.

　　9 Fujino T, Yamazaki Y, Largaespada DA, Jenkins NA, Copleland NG, Hirokawa K and Nakamura K. Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes. Exp. Hematol. 29:856-863, 2001.

　10 Hirokawa K and Goto S. Research on Biomedical Gerontology in Japan. Exp. Gerontol. 36:1581-1597, 2001.

　11 Utsuyama, M., Seidler, H., Kitagawa, M., Hirokawa, K., Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice. Mech. Ageing Dev. 122:341-35, 2001.

　12 Nakai D, Yuasa S, Takahashi M, Shimizu T, Asaumi S, Isono K, Takao T, Suzuki Y, Kuroyanagi H, Hirokawa K, Koseki H, Shirasawa T. Mouse homologue of Coq7/Clk-1, longevity gene in C.Elegans, is essential for coenzyme Q sysnthesis, maintenance of mitochondrial integrity and neurogenesis. BBRC 289:463-471, 2001.

　13 Nakajima T, Akiyama Y, Shiraishi J, Arai T, Yanagisawa Y, Ara M, Fukuda Y, Sawabe M, Saitoh K, Kamiyama R, Hirokawa K and Yuasa Y. Age-related hypermethylation of the hMLH1 promotor in gastric cancers. Int. J .Cancer 94:208-211, 2001.

　14 Kitagawa M, Aizawa S, Sado T, Yamaguchi S, Suzuki T, Hirokawa K and Ikeda H. A gene therapy model for retrovirus-induced disease with a viral env gene: expression-dependent resistance in immunosuppressed hosts. Leukemia 15:1779-1784, 2001.

　15 Yamada Z, Kitagawa M, Takemura T and Hirokawa K. Effect of maternal age on incidences of apoptotic and proliferative cells in trophoblasts of full-term human placenta. Mol. Hum. Reproduction 7:1179-1185, 2001.

　16 Yamaguchi S, Kitagawa M, Inoue M, Tejima Y, Kimura M, Aizawa S, Utsuyama M and Hirokawa K. Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia. Mech. Ageing Dev. 122:219-232, 2001.

　

[Graduate School, School of Medicine]

［TOKYO MEDICAL AND DENTAL UNIVERSITY］