Editorial Slides VP Watch –June 26, 2002 - Volume 2, Issue 25

Complement InhibitorA Potential Therapy for Prevention or Stabilization of

Vulnerable Plaque ?

Many components of innate and adaptive immune system are active in atherosclerotic plaques (as a chronic inflammatory process).

The complement system is one of the most important humoral systems mediating many reactions that contribute to host defense and initiating and amplifying inflammation, even in the pre-immune phase where specific antibodies and lymphocytes are not available.

Pang et al. in 1979 found that the complement system may be implicated in the pathogenesis of cholesterol-induced atherosclerosis in rabbits. 2

Endothelial cell damage causes complement activation and endothelial cells overlying atherosclerotic plaques contain C3 and C5b-9 antigens.

In 1987 Niculescu and colleagues showed deposition of terminal C5b-9 neo-antigens of complement system (indicator of complement activation) in atherosclerosis. 3

Niculescu et al. also found high levels of C5b-9 in the intimal thickening, fibrotic plaques and the corresponding media when compared with normal areas and fatty streaks intima. 6

Seifert et al. found a specific cholesterol-containing lipid particle in human atherosclerotic plaques that activates the alternative pathway of complement in a dose-dependent manner. 4

The protective effect of C6 deficiency on diet-induced atherosclerosis suggest that the terminal complement complex plays an important and critical role in the progression of atherosclerotic plaque. 7

• Colocalization of CRP with activated complement components in the atherosclerotic lesion suggests that CRP may be a major complement activating molecule in atherogenesis. 8

As reported in VP Watch of this week, Buono and colleagues compared extent and phenotype of diet-induced atherosclerotic plaque in LDLR-deficient mice with or without C3 deficiency. 9

This study shows that serum lipoprotein profiles and immunoglobulin levels were not significantly different between the 2 experimental groups (LDLR-KO mice with or without C3 deficiency). 9

They showed that a greater lipid-positive area in aortic arch sections in C3-deficient mice than in controls. 9

They also found higher macrophage accumulation, less SMC content, and less collagen content in aortic sections of C3-deficient versus control mice. 9

Conclusion

• Plaque maturation beyond the foam cell stage is dependent on an intact complement system.

• Complement activation should be considered when evaluating the mechanisms and prognostic significance of other inflammatory parameters associated with atherosclerosis, including CRP and humoral immune responses.

Questions:• Why fatty streak lesions are increased in C3

deficient mice? Why C3 deficient plaques have more macrophage density?

• Knowing the role of both cell-mediated and humoral immune response in atherosclerosis, the question is which one is more important in plaque formation (largely present in normal people) and which one is more important in plaque complication (only happens in victims of athero-thrombotic events)?

Questions:• Can complement inhibitor be a potential therapy

for prevention / treatment of vulnerable plaque?

• Since a humanized, recombinant, single-chain antibody specific for human C5 is clinically available, it would be interesting to know the effect of complement inhibition on post-transplant vasculopathy (coronary atherosclerosis). 10

1) Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.2) Pang AS, Katz A, Minta JO. C3 deposition in cholesterol-induced atherosclerosis in rabbits: a possible etiologic role

for complement in atherogenesis. J Immunol. 1979 Sep;123(3):1117-22.3) Niculescu F, Rus HG, Vlaicu R.; Activation of the human terminal complement pathway in atherosclerosis. Clin

Immunol Immunopathol. 1987 Nov;45(2):147-55.4) Seifert PS, Hugo F, Tranum-Jensen J, Zahringer U, Muhly M, Bhakdi S. Isolation and characterization of a

complement-activating lipid extracted from human atherosclerotic lesions. J Exp Med. 1990 Aug 1;172(2):547-57.5) Complement activation and atherosclerosis.

Mol Immunol. 1999 Sep-Oct;36(13-14):949-55.6) Niculescu, F., Hugo, F., Rus, H.G., Vlaicu, R. and Bhakdi, S., 1987. Quantitative evaluation of the terminal C5b-9

complement complex by ELISA in human atherosclerotic arteries. Clin. Exp. Immunol. 69, pp. 477¯483 7) Schmiedt, W., Kinscherf, R., Deigner, H.P., Kamencic, H., Nauen, O., Kilo, J. et al., 1998. Complement C6

deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler. Thromb. Vasc. Biol. 18, pp. 1790¯1795.

8) Jan Torzewski; CRP: evidence for an active role in the pathogenesis of atherosclerosisBMC Meeting Abstracts: 2nd Hot Topic Workshop on CRP 2001, 1:012

9) Buono, C., Come, C. E., Witztum, J. L., Maguire, G. F., Connelly, P. W., Carroll, M., Lichtman, A. H. (2002). Influence of C3 Deficiency on Atherosclerosis. Circulation 105: 3025-3031

10) Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation. 1999 Dec 21-28;100(25):2499-506.

References