A new approach to immunosuppression at the complement level-hypothesis.
A conceptual hypothesis for the possibility of treatment of certain immunological diseases in which the classical pathway (CP) of complement (c) plays a role in the pathogenesis is presented. It is proposed that in the clinical situations in which CP activation primarily contributes to the disease activity, administration of F(ab)2 fragment of human monoclonal antibodies directed against the active site of human Cls may suppress the disease. The F(ab)2 fragment should be specific for the active site of Cls and should not be reactive with the rest of the molecule. Such a treatment is not likely to effect Cls or total CP levels, as the F(ab)2 fragment will react only when and as soon as the active site has been generated on a Cls molecule. The interaction of a F(ab)2 fragment with Cls is also not likely to cause activation of the C. Specific inhibition of Cls in this way is expected to prevent, in CP mediated diseases, the increase in vascular permeability due to Cls and generation of C fragments responsible for anaphylactic, chemotactic and exocytosis activities and thus suppression of tissue destruction and disease activity. The validity of this hypothesis could be tested in experimental models of C mediated diseases in rats using F(ab)2 fragments of rat monoclonal antibodies directed against rat Cls. These studies could also be carried out in mouse system. F(ab)2 fragments of monoclonal antibodies against the active site of Clr may also be used instead of those against Cls.
Asghar
S S
SS
Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.
Asghar
R A
RA
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D003167:Complement Activation; D003172:Complement C1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D007165:Immunosuppression Therapy / Q000379:methods*
D003172:Complement C1; D007140:Immunoglobulin Fab Fragments