The possibilities and pitfalls for anti-complement therapies in inflammatory diseases.
The complement system is a key component of innate immunity, acting to protect the host from micro-organisms such as bacteria and other "foreign" threats, including tumor cells. However, excessive activation of complement can injure the host and can even be life threatening. These toxic effects are caused primarily by the excessive production of the anaphylatoxins C3a and C5a during complement activation and excessive formation of membrane attack complex on the host cell membrane. Many inflammatory diseases, including rheumatoid arthritis and glomerulonephritis, are thought to involve excessive activation of complement, both for their development and perpetuation. Uncontrolled complement activation is also implicated in post-ischemic inflammation and tissue damage and in sepsis. Therefore, it is important to regulate the complement system to treat disease. There are still no broadly applicable agents for the therapeutic regulation of excessive complement activation. However, there are now some agents in the development that might provide useful anti-complement therapies in the near future. Current strategies include the use of neutralizing antibodies, small synthetic antagonists, soluble recombinant forms of the natural complement regulators, and gene therapies to control excessive complement activation. Here we describe these new agents, their strengths and weaknesses and progress in testing the agents in relevant animal models.
Mizuno
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Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Tenovus building, Heath Park, Cardiff CF14 4XN, UK. MIZUNOM1@cardiff.ac.uk
Morgan
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D003169:Complement Inactivator Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000096:biosynthesis / Q000502:physiology*; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003169:Complement Inactivator Proteins; D003165:Complement System Proteins