Vaccination or Immunoglobulin Administration in Atherosclerosis

The large body of evidence showing that the immune response plays a role in the progression of atherosclerosis suggests that manipulating the immune system represents a possible prophylactic or therapeutic avenue for this disease. In view of the pathogenic role of the Th1 response, altering the Th1/Th2 balance is an attractive idea, but the proatherogenic effects of IL-4 suggest that this approach is also risky (King et al., 2002; Davenport and Tipping, 2003). In recent years, the most encouraging data for the immunological manipulation of atherosclerosis stem from studies involving immunization with atherosclerosis-associated autoantigens or immunoglobulin treatment. As indicated above, several different antigens engaged in atherosclerosis have been reported. Modified LDL molecules, usually via oxidation, are formed throughout disease progression and elicit autoimmune responses. Interestingly, immunization with one of the antigens that result from the oxidation process, malondialdehyde-modified LDL, reduces atherosclerosis in several animal models (Palinski et al., 1995a; Ameli et al., 1996; Freigang et al., 1998; George et al., 1998; Zhou et al., 2001). Some of these studies suggest that protection depends upon the induction of high titer of antibodies that may interrupt oxLDL recognition by macrophages or increase the clearance of oxLDL (Freigang et al., 1998; Zhou et al., 2001). Because elevated antibodies in immunized animals are of the IgG isotype, T cells could also be involved.

Microbial antigens may also play a role in the pathogenesis of atherosclerosis. For instance, certain microbial infections such as Chlamydia pneumoniae have been frequently reported in patients with atherosclerosis and it has been suggested that molecular mimicry may exist between these bacteria and modified LDLs (Hansson, 2001; Binder et al., 2003). As described above, strong similarities exist between anti-oxLDL antibodies isolated from apoE-deficient mice and naturally occurring T15 antibodies that are protective against common pathogens such as pneumococci (Shaw et al., 2000). Immunization of LDLR-/- mice with Streptococcus pneumoniae resulted in the production of elevated levels of anti-oxLDL, decreased atherosclerotic lesions, and plasma antibodies from these mice prevented the binding of oxLDL to macrophages (Binder et al., 2003).

In addition to active immunization, passive administration of antiphospho-lipid antibodies can also improve disease in atherosclerosis-prone mice (Nicolo et al., 2003). We obtained a panel of antiphospholipid IgG monoclonal antibodies from (NZW x BXSB) F1 mice, a cross that spontaneously develops systemic autoimmunity reminiscent of lupus and APS (Monestier et al., 1996). We observed that biweekly administration of one such monoclonal antibody, FB1, prevents plaque formation in LDLR-/- mice when compared to PBS- or control antibody-treated animals (Nicolo et al., 2003).

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