Therapeutic inhibition of the early phase of complement activation.
The complement system is a key component of innate immunity against invading pathogens. However, undesired activation of complement is involved in inflammation and associated tissue damage in a number of pathological conditions, such as ischemia/reperfusion injury, autoimmune diseases, and rejection of allo- and xenografts. During recent years, various therapeutically active complement inhibitors have been developed. In vivo studies using these inhibitors underscored the value of complement inhibition in the prevention of tissue damage. The currently available complement inhibitors mainly target the effector phase of the complement system that is common to all three activation pathways. Such a complete block of complement activation breaks the innate anti-microbial barrier, thereby increasing the risk for infection. Therefore, the development of potent complement inhibitors that interfere in the recognition phase of a specific complement activation pathway will generate important novel possibilities for treatment. The present review is focused on molecules that are able to inhibit the function of C1q and MBL, the recognition units of the classical pathway and the lectin pathway of complement, respectively. The potential value of these molecules for the development of therapeutically active complement inhibitors is discussed.
Roos
Anja
A
Department of Nephrology, Leiden University Medical Center, The Netherlands. A.Roos@LUMC.NL
Ramwadhdoebé
Tamara H
TH
Nauta
Alma J
AJ
Hack
C Erik
CE
Daha
Mohamed R
MR
D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D015922:Complement C1q / Q000037:antagonists & inhibitors / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D003171:Complement Pathway, Classical / Q000187:drug effects*; D006801:Humans; D037601:Mannose-Binding Lectin / Q000187:drug effects / Q000378:metabolism
D003169:Complement Inactivator Proteins; D037601:Mannose-Binding Lectin; D015922:Complement C1q