The use of IKK inhibitor as a lymphocyte depleting agent (47.4)

Abstract

Abstract Purposes: Transcription factor NF-κB and its activating kinase IκB Kinase β (IKKβ) are critical for inflammation and innate immunity. In our previoius report, MLN120B, an IKKβ inhibitor, would cause neutrophilia in mice but their peripheral blood lymphocyte numbers were not affected. We tried other IKK inhibitors; however, we found that feeding with BMS-345541, a highly selective IKKβ inhibitor, would cause lymphopenia in mice. We explored the possibility of BMS-345541 as a therapeutic agent in depleting lymphocytes. Results: To characterize how BMS-345541 affects lymphocyte homeostatsis, C57BL/6 mice received vehicle, or BMS-345541 oral gavage once daily at different dose (10, 25, 50, and 100 mg/kg body weight in 3% Tween 80), and mice were sacrificed on day 3 or day 5. We collected the peripheral blood for blood cell counts and also collected spleen and lymphnodes for histology examination. The lymphocytes, but not neutrophils, were significantly decreased in mice received BMS-345541. Our preliminary results showed that the effect of BMS-345541 on lymphocytes were through apoptosis rather than trapping the lymphocytes in lymphoid organs. BMS-345541 affected both T cells and B cells. Conclusion: We conclude that oral administration of BMS-345541 would reduce lymphocyte counts and could be helpful in depleting lymphocytes in circulation, which would be useful as a therapeutic agent for lymphoproliferative disorder.