Immunopharmacology最新文献

Although complete and partial complement deficiencies are well described in humans and several spontaneous animal models, many questions have remained regarding the exact role that these deficiency states play in the observed clinical manifestations. Likewise, many important mechanistic questions cannot be addressed using patients or spontaneously arising animal models of deficiency states. To provide additional insights and create readily manipulable experimental systems, over the last 5 years mice have been created by several groups in which specifically targeted insertional mutagenesis has resulted in complete deficiencies of complement activation proteins, receptors or regulatory proteins. Many surprising findings have already been made using mice derived from these strategies, and clinically relevant studies have begun to provide great insights into human deficiency states. This review includes an overview of these complement deficient mice and highlights some of the important findings that have resulted from their creation. A discussion of future experimental directions thought to be important by this author then follows and concludes the review.

In addition to its essential role in immune defense, the complement system contributes to tissue damage in many clinical conditions. Thus, there is a pressing need to develop therapeutically effective complement inhibitors to prevent these adverse effects. This concept, though old, received little scientific attention until recently. Data from animal models of diseases that have been produced using complement-deficient, knockout, and transgenic animals, as well as data demonstrating that complement proteins are produced in many important tissue sites (including the brain) have attracted the interest of many basic research scientists and applied scientists from the biotechnology field and larger pharmaceutical firms. This resurgence of interest has generated a wealth of new information in the field of complement inhibition. In this article, we comprehensively review up-to-date information in the field of complement inhibitors.

Factor H is responsible for recognition of host cells and tissues and mediates discrimination among microbial pathogens during activation of the alternative pathway of complement (AP). Its unique structure of 20 SCR domains arranged in a flexible chain permits a variety of functional sites to interact with complement proteins and surface markers in a biological example of single-molecule combinatorial chemistry. In addition to the complement regulatory site located in the N-terminal four SCR domains, two other sites bind complement protein C3b and three sites appear to recognize a variety of polyanions that serve as host markers. Recent studies indicate that cooperativity among several C3b- and polyanion-binding sites influences the biological functions of factor H and that the degree of influence of each site varies on different cells. The engagement of one or more of the host marker recognition sites enables factor H to control activation of the AP. The absence of host-like markers allows AP activation, but many common pathogens have developed receptors for factor H or mimics of host markers of varying degrees of authenticity allowing them to escape detection by this innate defense system. Organisms using one or more of these evasive techniques include Neisseria gonorrhoeae, Streptococcus pyogenes, Yersinia enterocolitica, Trypanosoma cruzi, and the HIV virus.

The innate immune system and notably the complement (C) system play important roles in host defense to recognise and kill deleterious invaders or toxic entities, but activation at inappropriate sites or to an excessive degree can cause severe tissue damage. C has been implicated as a factor in the exacerbation and propagation of tissue injury in numerous diseases including neurodegenerative disorders. In this article, we review the evidence indicating that brain cells can synthesise a full lytic C system and also express specific C inhibitors (to protect from C activation and C lysis) and C receptors (involved in cell activation, chemotaxis and phagocytosis). We also summarise the mechanisms involved in the antibody-independent activation of the classical pathway of C in Alzheimer's disease, Huntington's disease and Pick's disease. Although the primary role of C activation on a target cell is to induce cell lysis (particularly of neurons), we present evidence indicating that C (C3a, C5a, sublytic level of C5b-9) may also be involved in pro- as well as anti-inflammatory activities. Moreover, we discuss evidence suggesting that local C activation may contribute to tissue remodelling activities during repair in the CNS.