Our research area is in between clinical and basic science, involving immunology, microbiology, and oncology. Persistent viral infection causes various diseases by inducing immunodeficiency, malignancy, autoimmunity, and inflammation. Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), and Human T-cell leukemia virus type-I (HTLV-I) causes adult T-cell leukemia (ATL) and various chronic inflammatory autoimmune-like diseases. To understand mechanisms of these diseases, investigation on host immunity is indispensable. Immune responses are usually protective but sometimes harmful for the host, and are important determinants for disease manifestation. The goal of our research is elucidation of the role of host immunity in the diseases in order to develop effective immunotherapy. We also investigate intracellular mechanisms of viral replication to target direct molecules for therapy.
1. Analysis of immunological risks for ATL development in HTLV-I-carriers.
2. Development of anti-tumor vaccine against ATL.
3. Immunological and molecular mechanism of HTLV-1-induced leukemogenesis.
4. Molecular mechanism of HIV replication especially related to HIV-1 integrase.
5. Experiments based on gene therapy to suppress HIV-1 replication.
① Development and clinical study of anti-ATL vaccine therapy with Tax peptide-pulsed autologous dendritic cells.
Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-I (HTLV-I)-infected T-cell malignancy with poor prognosis. We developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy in collaboration of Tokyo Medical and Dental University, National Kyushu Cancer Center, and Kyushu University. The vaccine consists of autologous dendritic cells pulsed with Tax peptides corresponding to the CTL epitopes. Two of three patients administered with the vaccine achieved partial and complete remission without severe side effects. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL（Suehiro, Y., Hasegawa, A., et al. Br J Haematol, 2015）(Kannagi, M., et al. Cancer Sci, 2019).
② Involvement of innate immune response in HTLV-1 pathogenesis.
There are several enigmas in HTLV-1 pathogenesis. The level of HTLV-1 expression in infected cells is very low in vivo but rapidly induced in vitro. Despite the low viral expression, NFκB is constitutively activated, which plays an important role in leukemogenesis of adult T-cell leukemia/lymphoma (ATL). In addition, the combination therapy of AZT/IFN-a used for ATL outside Japan, while its transient anti-ATL mechanism has been unclear because HTLV-1-infected cells are resistant to this therapy in vitro. We found that host innate immune responses against HTLV-1 are involved in these long-puzzling phenomena. (Kinpara, et al. J Virol. 2009, Retrovirol, 2013, Leukemia, 2015). Furthermore, our findings elucidated that IL-10-dominant microenvironment is critical for HTLV-1 leukemogenesis partly explaining how HTLV-1 induces totally different lymphoproliferative or inflammatory diseases without differences in viral strains (Sawada, et al. PLOS Pathog, 2017). These findings indicate that both innate and acquired immune response against HTLV-1 are deeply involved in HTLV-1 pathogenesis (Kannagi, et al. Retrovirology. 2019).
③ Novel molecular basis to regulate HIV-1 replication.
Reverse transcription of viral genomic RNAs into DNA forms followed by integration of the viral DNA into host cell chromosome is an essential step for retroviral replication including human immunodeficiency virus type 1 (HIV-1). We have proposed that essential roles of integrase (IN) during reverse transcription step which could be the next target for novel anti-HIV drug development (Masuda. Front Microbiol, 2011). Recently we found that critical contribution of HIV-1 IN in facilitating reverse transcription is exerted through the IN precursor fusion form with reverse transcriptase (RT) (Takahata et al., J. Virol. 2017). Furthermore, we established in vitro cell-free HIV-1 reverse transcription assay to delineate the contribution of other cis- and trans-acting candidate factors in regulating HIV-1 reverse transcription. We revealed unprecedented roles of the 5’-end nucleotide of HIV-1 genomic RNA for reverse transcription (Masuda et al, Sci. Rep. 2015, Huang et al, BBRC. 2019). These studies have provided novel molecular basis and cocept to regulate HIV-1 replication.
① For under graduate students of the medical school, we participate in education of basic immunology I, and II, the project semester, and the preclinical clarkship.
② Graduate students are trained for basic skills in the field of immunology and virology to handle biohazard materials. We provide the opportunity to research for mechanisms of the retro-virus-mediated diseases and development of immunological therapeutics. All the stuffs and students participate in maintenance of the laboratory and periodical seminars to discuss about their own studies and keep up with the latest knowledge and information in the area.
Lectures & Courses
We always think of the clinical significance of the results of basic research. We try to find an effective therapy by approaching from basic research to understand the disease mechanisms and solve the problem. The disease mechanisms that we study include leukemogenesis, inflammation, immunosuppression, and autoimmunity in persistent virus infection. Through these studies, we contribute to clinical therapies as well as medical sciences.
Clinical Services & Other Works
We held the 5th Annual Meeting of Japanese Society of HTLV-1 Associated Diseases in Tokyo on Aug 31 through Sept 2, 2018.
We developed an anti-ATL immunotherapy (Tax peptide-pulsed dendritic cell vaccine), which is under clinical studies in collaboration with National Kyushu Cancer Center and Kyushu University. We evaluate anti-tumor and anti-virus T-cell responses in HTLV-1-infected patients with or without various therapies including the immunotherapy and hematopoietic stem cell transplantation, in response to requests from clinical doctors.