Simultaneous Targeting of IRE1a in B Cells and Macrophages for Lupus Therapy

描述（由申请人提供）：超过200万美国人患有狼疮，这是一种广泛存在的终身自身免疫性疾病。B淋巴细胞在狼疮中的有害作用可以通过在患者中发现高水平的致病性抗核自身抗体（ANAs）来证明。抑制B细胞自身抗体的产生已被认为是狼疮的一种治疗策略。此外，骨髓细胞，特别是巨噬细胞和中性粒细胞，通过产生促炎细胞因子和趋化因子，对狼疮的发生和进展有重要贡献。无论是阻断骨髓细胞运输还是抑制其产生炎性细胞因子的能力，都可以减轻动物模型和人类患者狼疮的临床症状。我们已经证明，肌醇要求酶1α (IRE1α)是主要的未折叠蛋白反应（UPR）传感器，是B细胞分化为浆细胞所必需的。最近，我们发现抑制IRE1α可抑制巨噬细胞和中性粒细胞产生炎性细胞因子，并保护小鼠免受炎性关节炎的侵害。此外，我们已经获得了令人振奋的初步证据，表明狼疮患者外周血白细胞中ire1 α-介导的UPR通路升高。通过遗传和药理学方法，我们发现在狼疮动物模型中，IRE1α是B细胞分化为血浆和自身抗体产生所必需的，这表明IRE1α是狼疮独特、高效的治疗靶点。此外，我们还鉴定出一种特异性的、无毒的IRE1α抑制剂4μ8c，可以有效地抑制IRE1α

DESCRIPTION (provided by applicant): More than 2 million Americans suffer from lupus, a widespread and life-long autoimmune disease. The detrimental role of B lymphocytes in lupus is evidenced by high levels of pathogenic antinuclear autoantibodies (ANAs) found in the patients. Suppression of autoantibody production by B cells has been considered as a therapeutic strategy for lupus. In addition, myeloid cells, in particular macrophages and neutrophils, contribute significantly to lupus development and lupus progression by producing pro-inflammatory cytokines and chemoattractant factors. Either blocking myeloid cell trafficking or suppressing their ability in producing inflammatory cytokines can reduce the clinical symptoms of lupus in both animal models and human patients. We have shown that inositol-requiring enzyme 1 alpha (IRE1α), the primary Unfolded Protein Response (UPR) transducer, is required for B cell differentiation into plasma cells. More recently, we discovered that inhibition of IRE1α suppressed inflammatory cytokine production by macrophages and neutrophils and protected mice from inflammatory arthritis. Further, we have obtained provocative preliminary evidence that the IRE1α-mediated UPR pathway is elevated in the peripheral leukocytes from lupus patients. Through both genetic and pharmacological approaches, we found that IRE1α is required for B cell differentiation into plasma and autoantibody production in the Lupus animal model, suggesting that IRE1α represents a unique, high-efficient therapeutic target for lupus. Additionally, we have identified a specific, non-toxic IRE1α inhibitor, 4μ8c, which can efficiently suppress antibody production by B cells and pro-inflammatory cytokine production by macrophages and neutrophils. Based on our recent discoveries and preliminary studies, we propose that suppression of IRE1α can repress production of both auto-antibodies by plasma cells and pro-inflammatory cytokines by macrophage/neutrophil and thus protect from the development of lupus. The current proposed study is to use both genetic and pharmacological approaches to evaluation the pre-clinical therapeutic efficacy of IRE1α suppression in lupus treatment (Aim 1) and to delineate the underlying molecular mechanisms of IRE1α in promoting autoantibody production by B cells (Aim 2) and pro-inflammatory cytokine production by myeloid cells (Aim 3) during lupus development. The proposed studies will not only demonstrate a novel therapeutic strategy and a potential drug for lupus, but will also contribute to a better understanding of the molecular basis underlying autoimmune responses associated with auto-antibodies and pro-inflammatory cytokines.