The complement system #2

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Front Biosci 2000 Sep 1;5:E63-81

Therapeutic inhibition of the complement system. Y2K update.

Asghar SS, Pasch MC

Division of Biochemistry and Immunology, Department of Dermatology,

Academic Medical Centre, University of Amsterdam, Amsterdam, The

Netherlands. s.s.asghar@...

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 Barre 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.