BZ Series Contributes to Understanding the Pathological Model of Asthma

Today, disorder treatment drawing on new research findings is seeing rapid progress as we understand more about how human immunity works. New treatment approaches have been considered from the aspect of the immune system for not only allergies but also for refractory diseases such as cancers and cardiovascular diseases. While research institutes worldwide are engaged in fierce competition in the R&D in this field, Chiba University has been seamlessly working on the entire process from the latest basic research to translational research that leads to clinical studies. Since fiscal 2008, the University has been promoting the Global COE Program as an international research hub for immune system regulation toward disease control. Spearheaded by Dr. Toshinori Nakayama, Professor of Immunology and leader of the center, Chiba University is focusing on the cultivation of able researchers and on research to overcome a range of refractory diseases. The efforts to establish advanced medical care are being undertaken at a rapid pace.

As a leading expert in the basic research in the field of immune system formation, Dr. Nakayama has contributed to uncovering the basic principles and mechanisms of acquired immunity.T cells, a type of immune cell, are known to differentiate into helper T cells. Dr. Nakayama has provided an explanation to the functions that these cells have.
As his new research theme, Dr. Nakayama is working on understanding, at a genetic level, the mechanism of how helper T cells, such as Th1 and Th2 cells, differentiate into memory cells. Dr. Nakayama says, “While we have expanded our knowledge of acquired immunity, there are yet more unknown facts. How immunological memory forms—the essence of acquired immunity—is hardly known, and as a researcher, I want to get to the bottom of this mechanism at molecular and genetic levels. These research findings will likely and eventually lead to a permanent cure for allergies and the development of influenza vaccinations that can be effective for a lifetime with just one injection,” explaining the significance of the research theme.
On the foundation of many years of basic research, Dr. Nakayama is also working on applied studies aimed at immune cell therapy. One of those studies is research into an innovative therapy using NKT cells, referred to as the fourth lymphocyte following T cells, B cells, and natural killer (NK) cells. This therapy is anticipated to be effective in cancer treatment. In particular, a clinical trial started in around 2001 for lung cancer, producing significant treatment outcomes such as shrinkage of cancer tumors. Application of this method is also under consideration as a treatment for head and neck cancer. An application in these fields is the first step toward the application of the treatment on a wider scale.
“Conventional standard surgeries, radiology, and chemotherapy had limits with regards to lung cancer. This is because lungs are an organ with a sponge-like structure and have a large amount of blood flow, so that by the time the cancer shows up as a shadow on a CT or on other diagnostic imaging, it is often many tiny metastases (less than a few millimeters) inside the lungs. Those eventually grow and cause the lung cancer to recur. Without lungs, humans cannot breathe and will die, so we cannot preventively resect the entire lungs like a full gastrectomy in the case of advanced stomach cancer. There is a limit to controlling cancer cells with drugs.
In that sense, treatment using the patient’s own immune system is promising. Even compared to other treatments such as post-surgery chemotherapy, there is already evidence of patient life expectancy being extended significantly. Currently, we are conducting clinical trials to verify the regimen and dosage of NKT cells while steadily advancing the research on the therapy. Preparation for application as advanced medical care is also in progress, and today we have about 100 patients receiving the therapy.”
There are hopes for the effectiveness of the treatment of cancer using immune cells. Furthermore, this treatment has a great advantage in that it is safe and minimally invasive. “Unlike existing anticancer drugs, this approach is characterized by it being less traumatizing to patients. Side effects are generally just a slight fever, if any,” says Dr. Nakayama.
As to what he expects the future of this research to be, he states that “immune system-based therapy will make possible a permanent cure for cancers as custom-made medical care and will greatly change the way medical care is provided, shifting from cancer treatment to prevention.”
As another new approach following treatment for allergies and cancers, Dr. Nakayama is also thinking about treating cardiovascular disorders, including arteriosclerosis, from the perspective of the immune system. According to Dr. Nakayama, “treatment using the immune system will be possible by framing arteriosclerosis as an inflammation inside a blood vessel.” He says that he “wishes to put more efforts into cultivating researchers in this field alongside working on joint studies with researchers specializing in arteriosclerosis and inflammation in the blood vessels, with a vision of where things can be 10 and 20 years down the road.”

Chiba University is promoting the Global COE Program, for which Dr. Nakayama has served as the center’s leader since fiscal 2008. The program is designed to be an international research hub for immune system regulation toward disease control. The center consists of the Graduate School of Medicine, the Graduate School of Pharmaceutical Sciences, the University Hospital, and the following external institutes: the RIKEN Research Center for Allergy and Immunology and the National Institute of Radiological Sciences. The research center conducts research on the immune system and aims to achieve therapeutic research and development for refractory immunity-related diseases by means of regulating the immune system. As an educational institution, the Global COE Program at Chiba University is also focusing its efforts on cultivating young researchers engaged in immunology research.
Looking at the role of each organization, while the two Graduate Schools at Chiba University are engaged in research on therapeutics based on acquired immunity, RIKEN works on therapeutics based on natural immunity. Conventionally, research on immunity was centered on acquired immunity, but the importance of natural immunity has been reaffirmed in recent years. Through close collaboration, the research performed by Chiba University and RIKEN has advanced therapeutics based on both immune responses.
As for clinical studies, in addition to the University Hospital undertaking clinical trials on immunological disorders led by the Center for Advanced Medicine, the National Institute of Radiological Sciences is working on the development of combination therapies that use both immune responses and charged particle therapy to combat cancer. The center’s use of this combined therapy is a worldwide first and it is anticipated to be beneficial as a less invasive therapy for cancer.
“Japan, the U.S., and Europe are on par with each other regarding research into the immune system. In pursuit of being a global frontrunner in this field, this is an ideal environment. While we promote the Global COE Program, we can deliver new therapeutic concepts to the world as an international education and research hub for immune system regulation toward disease control,” says Dr. Nakayama.

Suited to a research center adopted for the Global COE Program, Dr. Nakayama’s lab is equipped with the latest cell separation systems and other equipment necessary for research into the pathological models of immunological diseases. Among such installations, the KEYENCE BZ Series fluorescence microscope is used to its full potential for cell observation.

All immune cells originate in the bone marrow and are produced from stem cells to become macrophages, T cells, B cells, natural killer (NK) cells, and other white blood cells. B cells further become antibody-forming cells, which produce antibodies that fight antigens.
T cells differentiate into helper T cells and killer T cells. The former gives instructions to B cells to produce antibodies and to killer T cells to attack antigens.
In a healthy person’s blood, lymphocytes account for about one-third of the white cells. Most of the lymphocytes are T cells, B cells, and NK cells, but NKT cells also exist in a very small percentage of below 0.1%. This is said to have an important role in the immune system.