Toubai T.,University of Michigan |
Hou G.,University of Michigan |
Mathewson N.,University of Michigan |
Liu C.,Florida College |
And 12 more authors.
Blood | Year: 2014
Activation of sialic-acid - binding immunoglobulin-like lectin-G (Siglec-G) by non-infectious damage-associated molecular patterns controls innate immune responses. However, whether it also regulates T-cell - mediated adaptive immune responses is not known. Graft-versus-host reaction is a robust adaptive immune response caused by allogeneic hematopoietic cell transplantation that have been activated by antigen-presenting cells (APCs) in the context of damaged host tissues following allogeneic hematopoietic cell transplantation. The role of infectious and noninfectious pattern recognition receptor - mediated activation in the induction and aggravation of graft-versus-host disease (GVHD) is being increasingly appreciated. But the role of pathways that control innate immune responses to noninfectious stimuli in modulating GVHD has heretofore not been recognized. We report that Siglec-G expression on host APCs, specifically on hematopoietic cells, negatively regulates GVHD in multiple clinically relevant murine models. Mechanistic studies with various relevant Siglec-G and CD24 knockout mice and chimeric animals, along with rescue experiments with novel CD24 fusion protein demonstrate that enhancing the interaction between Siglec-G on host APCs with CD24 on donor T cells attenuates GVHD. Taken together, our data demonstrate that Siglec-G - CD24 axis, controls the severity ofGVHDand suggest that enhancing this interaction may represent a novel strategy for mitigating GVHD. © 2014 by The American Society of Hematology.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 865.48K | Year: 2004
DESCRIPTION (provided by applicant): The ultimate goal of our research and development program in multiple sclerosis (MS) is to develop a novel MS drug that targets CD24, a GPI-anchored surface glycoprotein that served as a critical checkpoint for MS
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.15K | Year: 2011
DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is among the most common autoimmune diseases. The current treatment for RA is mainly by targeting tumor-necrosis factor (TNF). Despite the remarkable efficacy, significant portion of RA patients are not responsive to this class of drugs. Therefore, there is an urgent need to develop therapeutic that can complement existing therapeutic biologics. Recently, it has been suggested that danger (or damage)-associated molecular patterns (DAMPs), a group of intracellular component released from necrotic cells, such as HMGB1 and HSP70, may be involved in the pathogenesis of RA. In consistency with this notion, partial inhibition of collagen-induced arthritis was achieved by administration of anti-HMGB1 mAb. These data support the notion that tissue destruction by autoreactive cells can form a vicious cycle of chronic inflammation, as is the case of RA. However, it appears that the impact of anti-HMGB1 antibodies remains modest. The relatively minor effectsare to be expected as multiple DAMPs are expected to be released during autoimmune tissue damage. On the other hand, we have recently identified that CD24-Siglec 10 mediate a negatively regulatory pathway that selective regulates host response to DAMP 1.Since the CD24 binds to multiple DAMPs, including HMGB1, HSP70, HSP90 and nucleolin, it is conceivable that CD24 fusion proteins can be explored for therapy of RA. As the proof of concept, we have shown that CD24Fc, a fusion protein consisting extracellular domain of human CD24 and the Fc of human IgG1, protected mice against RA induced by a cocktail of anti-collagen antibodies. Based on this exciting observation, we will use collagen-induced arthritis (CIA) model, the gold standard for clinical developmentof RA drug, to confirm the therapeutic effect of CD24Fc and compare CD24Fc with Enbrel, the clinically used soluble receptor for TNFa. In addition, we will establish an in vitro model to demonstrate the mode of action of the CD24Fc, as detailed in two specific aims. Specifically, we will establish the therapeutic effect of CD24Fc using CIA model and determine whether the therapeutic efficacy of CD24Fc can be used in combination with TNFa antagonist to increase therapeutic efficacy. Then we will determine the CD24 expression in DC and macrophages among the inflammatory cells and identify the population that produces inflammatory cytokine. We will also test whether CD24Fc inhibit the production of inflammatory cytokines on these cells. The completion of thisproposal will not only substantiate the therapeutic potential of CD24Fc, but also provide a mechanism of action for CD24Fc and facilitate the down-stream drug development. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is among the most common autoimmune diseases and it affects 0.5-1% of humans. Despite the remarkable efficacy of the current therapies that mostly target on TNF-alpha, significant portion of RA patients are not responsive to these treatments. The ultimate goal of this application is to develop a novel biological therapeutics, namely CD24Ig Fc fusion protein, by targeting danger (or damage)-associated molecular patterns (DAMPs), which was recently been demonstrated to be involved in the pathogenesis of Rheumatoid arthritis.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 116.42K | Year: 2002
The Ras oncogene is one of the most frequently mutated oncogenes in human cancer. Approximately 30 percent of human cancers contain activated Ras mutations. Extensive efforts have been made to identify Ras inhibitor as a putative cancer therapy with the most promising progress of farnesyl transferase inhibitor. Farnesylation of Ras is essential for its biological functions. However, many small GTPases, which play important roles in cellular functions, also require farnesylation or isoprenylation. Therefore, these inhibitors may have none specific effects due to inhibition of other small GTPases. A major long-term goal of OncoImmune is to develop therapeutic agents for treatment of cancers. The main goal of this proposal is to demonstrate that GDP-bound Ras mutant, RasN17N69, can be used to inhibit cancer cell growth in vitro and in vivo. This proposal is based on our novel observations that RasN17N69 inhibits cell transformation but not growth of normal cells. Furthermore, the proposal uses a new technology of protein transduction to test this hypothesis in vitro and in vivo. The following specific aims will be accomplished in this proposal. 1. To demonstrate that GDP-bound mutant RasN17N69 can suppress transforming phenotypes of tumor cells. 2. To provide evidence that RasN17N69 can inhibit tumor growth in animal model.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 145.25K | Year: 2003
DESCRIPTION (provided by the applicant): It is generally accepted that autoreactive T cells are involved in pathogenesis of multiple sclerosis (MS). We have shown that CD24 gene controls the effector function, but not the induction, of the autoreactive T cells in the mouse model of multiple sclerosis, the experimental autoimmune encephalomyelitis. We have also shown that injection of fusion protein comprising of the extracellular domain of the CD24 protein results in significant reduction in the clinical score of the EAE. More recently, we discovered that in bone marrow chimera mice, bone marrow-derived cells could replace the vascular endothelial cells in the CNS. To explore the potential clinical application of these observations to the therapy of multiple sclerosis, we have established novel in vitro culture protocol to produce bone marrow-derived endothelial cells. We have found that they can migrate into the CNS after adoptive transfer and form neovasculature in the CNS. Moreover, we have produced lentiviral vector that can transduce the CD24Ig gene into the endothelial cells in vitro. In this proposal, we will test whether the endothelial cells expressing CD24Ig can be used for the therapy of EAE in mouse model. Specifically, we will address two questions: 1). Are mice reconstituted with endothelial cells expressing CD24Ig resistant to pathogenic autoreactive T cells in CNS? We will transduce bone marrow derived endothelial cells from C57BL/6 mice with CD24Ig gene and test whether injection of the CD24Ig-transduced endothelial cells will result in resistance to autoreactive T cells. We will also compare the efficacy of CD24IgG to that of CD241gM that should have higher valences and therefore may have higher avidity for the potential CD24 ligands. 2). Can the CD24Ig-transduced endothelial cells provide therapeutic effect in mice with relapsing remitting EAE? We will transduce bone marrow derived endothelial cells from SJL mice with CD24Ig gene. We will inject the CD24Ig-transduced endothelial cells into SJL mice with ongoing EAE and test if these cells can prevent EAE relapse. Our proposed work will test the concept of using endothelial cells as a gene vehicle for the treatment of multiple sclerosis. If succeed, this will provide a new approach for therapy of organ-specific autoimmune diseases in general and the multiple sclerosis in particular.