Institute of Biomedical Research and InnovationImmunology, Laboratory of Immunology
Department of Immunology
Rebalancing the immune system, reviving the healthy life
Dysregulation of the immune system triggers a wide variety of diseases. On one hand, the immunocompromised state allows the outgrowth of pathogens, such as bacteria and viruses, and even cancer cells. On the other hand, overwhelming immune response led by uncontrolled immune cells can cause proinflammatory disorders, including allergic and autoimmune diseases. The objective of our research is to develop a novel therapeutic approach to these 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. Blockade of immune checkpoints promotes immune activities; therefore, it has been used in the working treatment of cancer patients. Conversely, pharmacological stimulation of immune checkpoints will be able to attenuate immune activities, thereby alleviating various proinflammatory disorders.
- Research content
To prevent excessive inflammatory tissue damage, physiological negative feedback mechanisms are activated in the course of inflammation and downregulate proinflammatory response. Such immunoregulation is so critical that the deficiency of one of the immune checkpoint mechanisms results in severe and sustained inflammation. For example, PD-1-deficient mice spontaneously develop various inflammatory disorders. Although the function of immune checkpoints is indispensable in tissue protection from excessive inflammation, tumors have been found to make use of these immunosuppressive mechanisms in protecting themselves from anti-tumor immune response. Inhibitors of immune checkpoints have been applied to promote anti-tumor immunity in the tumor microenvironment. Clinical success of this strategy represented by blocking antibodies to PD-1 opened a path to the novel therapy of cancer. Thus, immune checkpoint mechanisms are promising targets of immunotherapy that can dramatically change the direction of immune response and the outcome of diseases.
Opposite to cancer, overwhelming immune response causes various autoimmune disorders. Immune checkpoints play a significant role in the negative regulation of autoimmune response, since their disruption results in overwhelming inflammation as discussed above. To prevent unwanted tissue damage 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. These “agonistic” antibodies will be potentially useful in the treatment of autoimmune diseases.
Anti-cancer treatment with the immune checkpoint-blocking therapy often accompanies inflammatory complication due to overcompensation of the systemic immune system. 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. The same factors will affect the vulnerability to spontaneous development of autoimmune diseases. 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.
Selected recent publications
Ohta, A. and Sitkovsky, M. Extracellular adenosine-mediated modulation of regulatory T cells. Front. Immunol. 5: 304, 2014.
Hatfield, S.M., Kjaergaard, J., Lukashev, D., Belikoff, B., Schreiber, T.H., Sethumadhavan, S., Abbott, R., Philbrook, P., Thayer, M., Shujia, D., Rodig, S., Kutok, J.L., Ren, J., Ohta, A., Podack, E.R., Karger, B., Jackson, E.K., and Sitkovsky, M. Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection. J Mol Med (Berl) 92:1283-1292, 2014.
Hatfield, S.M., Kjaergaard, J., Lukashev, D., Schreiber, T.H., Belikoff, B., Abbott, R., Sethumadhavan, S., Philbrook, P., Ko, K., Cannici, R., Thayer, M., Rodig, S., Kutok, J.L., Jackson, E.K., Karger, B., Podack, E.R., Ohta, A., Sitkovsky, M. Immunological mechanisms of the anti-tumor effects of supplemental oxygenation. Sci Transl Med 7: 277ra30, 2015.
Ohta, A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol 7: 109, 2016.
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.
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.
Ohta, A. Oxygen-dependent regulation of immune-checkpoint mechanisms. Int Immunol 2018. doi: 10.1983/intimm/dxy038.