Institute of Biomedical Research and InnovationDepartment of Immunology, Laboratory of Immunology
A researcher / Research focus
Rebalancing the immune system, reviving the healthy life
Dysregulation of the immune system triggers a wide variety of diseases. The objective of our research is to develop a novel therapeutic approach to inflammation-related diseases by controlling the intensity of immune activities to appropriate levels. The human body has physiological feedback mechanisms that downregulate proinflammatory activities. These immunoregulatory mechanisms, known as immune checkpoints, are promising targets of therapeutic intervention. Pharmacological stimulation of immune checkpoints will be able to attenuate excessive immune activities, thereby alleviating various proinflammatory disorders. We also aim to discover diagnostic markers, which indicate early inflammatory changes. Early recognition of the patient’s potential risk for eventual proinflammatory pathogenesis should be useful in determining clinical approaches.
- Research focus
- Publications and Activities
The immune system is equipped with a variety of activating and inhibitory mechanisms with which the type and intensity of immune responses are controlled to appropriate levels. However, in some occasions, immunocompromised state allows the outgrowth of pathogens, such as bacteria, viruses and cancer cells. Dysfunction in the immunoregulation may cause overwhelming immune response that triggers pathogenesis of proinflammatory disorders, including allergic and autoimmune diseases.
PD-1 represents physiological immunoregulatory mechanisms. As observed in PD-1-deficient mice spontaneously developing inflammatory disorders, PD-1-dependent immunoregulation is crucial to the prevention of excessive inflammatory response. PD-1 expression is very limited in normal conditions, but it is notably upregulated in activated immune cells, suggesting that the PD-1 pathway is a physiological negative feedback mechanism in the course of inflammation. Indeed, tumors take advantage of these physiological immunosuppressive mechanisms to protect themselves from anti-tumor immune response. Inhibitors of PD-1 or other immune checkpoints have been applied to promote anti-tumor immunity in the successful treatment of cancer patients.
To prevent overwhelming inflammatory activities in autoimmune diseases, the function of immune checkpoint mechanisms may be enhanced enough to compensate for the immune overactivation. We aim to develop anti-PD-1 antibodies with immunosuppressive activity. Such “agonistic” antibodies are different from anti-PD-1 blocking antibodies, which are used in cancer treatment, but are capable of triggering intracellular signaling of PD-1. We developed the screening system of biologically-active anti-PD-1 antibodies, and screening of antibodies identified some agonistic antibodies along with blocking antibodies.
When applied to inflammatory disease models in mice, the PD-1 agonists demonstrated significant anti-inflammatory effects. In a graft-versus-host disease model, anti-PD-1 agonist antibody strongly suppressed the disease as observed in the prevention of weight loss and donor T cell proliferation. These results indicate that our PD-1 agonists may be promisingly useful in the treatment of inflammatory diseases. We will characterize immunosuppressive effects of the PD-1 agonists in order to understand the type of diseases that may respond well to this treatment.
Anti-cancer treatment with immune-checkpoint blockers often accompanies inflammatory complication due to overcompensation of the systemic immune system (immune-related adverse events). The ultimate goal of immunotherapy is to guide the immune response to the appropriate intensities in patients; however, the individuals respond to the same treatment differently dependent on their immune status and predisposition to autoimmunity. We investigate potential diagnostic markers, which enable the prediction of overactive immunity and autoimmunity in tissues. These markers may differentiate individuals at a higher risk of inflammatory disorders, which may develop spontaneously or after the immunoenhancing treatment.
Publications and Activities
- 1) Ohta, A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol 7: 109, 2016.
- 2) Abbott, R.K., Thayer, M., Labuda, J., Silva, M., Philbrook, P., Cain, D.W., Kojima, H., Hatfield, S., Sethumadhavan, S., Ohta, A., Reinherz, E.L., Kelsoe, G., and Sitkovsky, M. Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination. J Immunol 197: 4014-4020, 2016.
- 3) Abbott, R.K., Silva, M., Labuda, J., Thayer, M., Cain, D.W., Philbrook, P., Sethumadhavan, S., Hatfield, S., Ohta, A., and Sitkovsky, M. The Gs Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center. J Biol Chem 292:1211-1217, 2017.
- 4) Ohta, A. Oxygen-dependent regulation of immune-checkpoint mechanisms. Int Immunol 2018. doi: 10.1983/intimm/dxy038.
- 5) Kjaergaard, J., Hatfield, S., Jones, G., Ohta, A., and Sitkovsky, M. A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression. J. Immunol. 201: 782-791 (2018)