The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4 ؉ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigenspecific CD4؉FoxP3؉ regulatory T cells (Treg cells) with inhibition of the canonical NF-B1 transcription factor complex and activation of the alternative NF-B2 pathway. Treatment with ACE inhibitors induces abundant CD4؉FoxP3؉ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases. multiple sclerosis ͉ lisinopril ͉ FoxP3 ͉ AT1R
3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal–regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.
Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought IntroductionMonoclonal antibodies (mAbs) have revolutionized the treatment of cancer. The first approved mAb for this purpose, rituximab, a murine-human chimeric immunoglobulin G1 (IgG1) antibody against CD20, has become a standard treatment for patients with B-cell lymphomas.Despite tumor response rates to rituximab of up to 90% and decreased risk of death by as much as 36%, the majority of patients with advanced lymphoma still die of their disease, including 19 000 patients in the United States in 2009 alone. [1][2][3][4] Enhancing the efficacy of rituximab represents an opportunity to improve patient outcome. We have developed a strategy to enhance the antitumor activity of rituximab by augmenting antibody-induced cell killing.Several mechanisms of rituximab's antitumor action have been proposed, including direct induction of apoptosis, complementdependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and, possibly, induction of an adaptive immune response (a "vaccinal" effect). 5 Among these mechanisms, ADCC is believed to be of importance, particularly to the initial antitumor response. In vitro studies have shown that rituximab can induce ADCC of human lymphoma cell lines. 6 In murine xenotransplant lymphoma models, a role for ADCC in rituximab's efficacy was confirmed in studies using FcR-␥-chain-deficient mice, 7 as well as a neutralizing antibody against murine Fc␥R. 8 Further murine studies using CD20 mAbs have confirmed that monocyte-mediated ADCC is the primary, if not exclusive, mechanism through which normal and malignant B cells are depleted in vivo. 9-13 Finally, clinical results have shown that patients harboring an Fc␥RIIIA polymorphism with higher affinity for IgG1 have better responses to rituximab, further supporting the hypothesis that ADCC is an important in vivo mechanism of rituximab action in patients with lymphoma. 14,15 Natural killer (NK) cells are known to be important effector cells mediating ADCC. Binding of the NK-cell Fc receptor (Fc␥RIII, CD16) to the constant region of an antibody induces NK-cell activation. On activation, NK cells release cytotoxic granules, promoting tumor cell killing, and up-regulate the expression of several activation markers, including CD137. 16 In this study, we hypothesized that rituximab-induced ADCC could be specifically increased by using an anti-CD137 agonistic mAb to enhance NK-cell function.CD137 (4-1BB) is a surface glycoprotein that belongs to the tumor-necrosis factor receptor superfamily. 17 CD137 is an inducible costimulatory molecule expressed on a variety of immune cells, including activated CD4 and CD8 T cells, NK cells, monocytes, and dendritic cells. 18,19 On T cells specifically, CD137 functions as a costimulatory receptor induced on T-cell receptor stimulation. In this context, ligation of CD137 leads to increased T-cell proliferation, cytokine production, functional maturation, and prolonged ...
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