Inhibitory Receptors and Autoimmune Arthritis

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Rheumatoid arthritis (RA) is an inflammatory disorder characterized by autoimmunity. We propose a novel method for suppressing inflammation by upregulating and activating natural inhibitory receptors called leukocyte associated immunoglobulin-like receptors (LAIR). One of these, LAIR-1 (also called CD305) acts as a negative regulator of immune cell receptor signaling, suggesting that activating LAIR-1 receptors may lead to diminished autoimmune activity and less severe disease in patients with RA. We have further demonstrated that culture with vitamin D increases LAIR-1 on CD4+ T cells. The discovery of a new secosteroidogenic pathway initiated by P450scc that produces vitamin D3 hydroxyderivatives has opened new options in treatment for RA. We predict that upregulating Lair-1 by using new vitamin D3 hydroxyderivatives could lead to attenuation of the severity of arthritis using safer therapies than are currently available. We propose a set of experiments using murine models of autoimmune arthritis. Our central hypothesis is that inflammation can be downregulated by stimulation of the inhibitory receptor LAIR-1 and that vitamin D and its analogs enhance this suppression by upregulating LAIR-1. We also believe that the noncalcemic 20(OH)D3 will be as effective and less toxic than the classical form of vitamin D3 [1,25(OH)2D3]. To understand the mechanisms by which inhibitory receptors attenuate inflammation we propose the following specific aims: Specific Aim 1: To test the hypothesis that activation of the LAIR-1 inhibitory receptor leads to suppression of T cell cytokine production and that the inhibition is enhanced by vitamin D or the noncalcemic 20(OH)D3 analog. Specific Aim 2. Determine whether activation of LAIR-1 will attenuate autoimmune arthritis and whether vitamin D or 20(OH)D3 enhances this effect using two mouse models of arthritis: collagen-induced arthritis (CIA) and the IL-1 receptor antagonist deficiency IL-1Rn-/- spontaneous arthritis model (SAD). Specific Aim 3. To test the hypothesis that upregulation of LAIR-1 leads to suppression of T cell signaling by repressing the canonical T cell pathway and altering T cell cytokine production and that vitamin D or 20(OH)D3 will enhance this effect. Successful completion of these experiments will elucidate the mechanisms whereby treatment with new Vit D analogs leads to upregulation of the inhibitory receptor LAIR-1, ultimately inducing suppression of cytokine secretion and prevention of arthritis.