2012 General Immune System Function, New Treatments
The function of Orai1 in immune tolerance and lupus therapy
The Study and What it Means to Patients
Elevation of intracellular calcium concentration is essential to activate immune cells, and inhibiting the calcium increase causes profound immunosuppression. We’ve discovered a potentially therapeutic role of calcium inhibition that could particularly benefit lupus patients. We’re exploring whether treating mice with an inhibitor of a newly discovered subunit of calcium channel, a protein Orai1, induces regulatory T cells to prevent lupus autoimmunity while retaining protective immune responses to infection.
Calcium is critical component of the complex signalling circuitry inside immune cells that allows them to become activated. My colleagues and I recently identified a new molecular component of the pore-like channel that allows cells to replenish their calcium levels when immune cells become activated. Subsequent work in our lab has shown that blocking Orai1 in mice not only blocks immune cell activation, as you might expect, but also increases the number and potency of regulatory T cells. In theory these T cells could suppress unwanted immune responses in the longer-term, well beyond the time of treatment. So for lupus patients, Orai-inhibitors could have a dual beneficial effect. With our LRI novel research grant we will test this concept in lupus mice by treating them with an Orai1 inhibitor.
Orai1 is a new, unexplored drug target in lupus. The capacity of orai1-inhibitors to induce regulatory T regs is a novel early observation, which has not been investigated previously in any disease. Inhibition of Orai1 is a novel treatment strategy for lupus and other autoimmune diseases.
We plan to test the possibility that blocking Orai1, the pore component of CRAC (Ca2+-release-activated Ca2+) channels can be developed as therapy to shut down the immune system temporally to relieve the symptoms, and to increase immune tolerance in a long term. Analysis of severe combined immune deficiency (SCID) patients with a defect in Orai1 and knockout mice showed that Orai1 activity is crucial for the functions of diverse immune cells. These indicate that it is highly possible that blocking Orai1 will relieve the symptoms of SLE during the treatment. Induction of long-term immune tolerance by inhibition of Orai1 is a novel aspect, however, it has a high chance of success because our preliminary data show; (i) blocking Orai1 activity can induce more Tregs with much higher expression levels of Foxp3. (ii) the frequency of Tregs were increased by Orai1 deficiency, and (iii) in an animal model of autoimmune diseases, very short period or even single injection of a small molecule blocker for Orai1 drastically ameliorated the symptoms. Together, these short- and long-term effects of blocking Orai1 provide an ideal and novel therapeutic strategy for SLE.