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.
The significance of the proposed work lies with the parallel use of animal models of arthritis to study a new treatment strategy for RA. In this application, we plan to use two murine models of arthritis to study the mechanism by which new safer hydroxyderivatives of vitamin D3 can upregulate an inhibitory receptor to suppress unwanted inflammatory responses in autoimmune arthritis. The purpose of the proposal is to delineate the mechanism of action by which autoimmunity is suppressed with the ultimate aim of developing safer and more effective treatments for RA.
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