Activation of
complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in
complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of
complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of
hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe
inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human
sepsis, post-operative myocardial dysfunction due to
reperfusion injury, severe capillary leakage syndrome after
bone marrow transplantation,
reperfusion injury after
lung transplantation,
burn, and cytotoxicity caused by
IL-2 therapy in
cancer.
Factor I has been used for the treatment of
factor I deficiency. Recombinant soluble forms of
membrane cofactor protein (MCP), and
decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in
immune complex mediate
inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of
complement namely
membrane cofactor protein (MCP),
decay accelerating factor (DAF) or CD59, are being produced for
transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-
transplantation in clinical practice a reality. Several recombinant variants of
complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits
complement and
carbohydrate Sle x moiety inhibits
selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress
ischemia/reperfusion injury, thermal
trauma, and
immune complex mediated
inflammation. They have also been shown to be effective in experimental models of
systemic sclerosis,
arthritis,
myasthenia gravis,
Guillain Barré syndrome and
glomerulonephritis.
Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of
autoantibody activity, suppression of
autoantibody production and inhibition of
complement activity, is being used in several diseases. These include autoimmune thrombocyopenic
purpura,
Kawasaki disease and several neurological diseases such as
myasthenia gravis and
Guillain Barre syndrome. In many uncontrolled small scale studies
intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of
complement will be one of the major approaches to combat many human diseases.