Generation of complement C9 conditional knockout mice and anti-C9 mAbs

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DESCRIPTION (provided by applicant): Complement is important part of the innate immune system and is arguably best known for its ability to lyse bacteria, enveloped viruses and eukaryotic cells through a macro- molecular structure known as the membrane attack complex (MAC). The MAC is composed of several complement proteins (C5b, C6, C7, C8 and C9), but C9 is the critical protein required for the pore-forming structure of the MAC. Because the complement system discriminates poorly between self and non-self under inflammatory conditions, inappropriate activation of complement and subsequent MAC-mediated destruction of self-tissues is a common feature of autoimmune disease. The evidence linking C9 to cell death in this setting is frequently circumstantial, based largely on immunohistochemical staining for C9 in postmortem tissue samples. However in some disease settings, such as demyelinating disease, there are clear discrepancies between the need for C9 and the MAC as important components of the pathogenic mechanism. This raises questions regarding how critical C9 is in demyelinating disease and in other autoimmune diseases where complement-mediated mechanisms are considered central to disease pathology. In addition, there are many unanswered questions regarding C9 biology. For example, does C9 contribute to normal development? What are the regulatory mechanisms for C9 gene expression? What are the C9-mediated signaling events generated on interaction with prokaryotic and eukaryotic membranes? Surprisingly, there are no murine-specific tools to address these questions. We propose to generate C9-specific monoclonal and polyclonal antibodies and conditional C9-deficient mice to provide much needed tools to directly assess of the role of C9 in autoimmune and inflammatory diseases. PUBLIC HEALTH RELEVANCE: The role of the complement component C9 in autoimmune and infectious disease remains poorly explored due to the lack of appropriate reagents. Studies in this application are designed to generate C9 conditional knockout mice and anti-C9 monoclonal antibodies.