Infections caused by the intracellular organisms, Chlamydia pneumoniae, Mycobacterium sp. and/or Helicobacter pylori, have been implicated as co-risk factors in atherosclerosis, but their exact roles in disease progression remain controversial. We propose to characterize the immunological shifts in atherosclerosis that would be accelerated by the infections. Type 1 helper T lymphocyte- (Thl-) immunity activates local macrophages (MQ) that kill the intracellular bacteria and also potentially damage endothelial tissue, which could initiate lesions at the early stages. Previous studies suggest that splenic prostaglandin E2-releasing MQ (PGE2-MQ) levels are increased with the progression of atherosclerosis and in infections. Since PGE2 is a powerful inducer of the Thl to Th2 immune shift, PGE2-MQ could make a major contribution to the pathogenesis of chronic stages of atherosclerosis. In this. regard, much attention has been directed to mycobacterial 65kDa-heat shock protein (HSP65), an immunodominant antigen having cross-reactivity with other bacterial and mammalian HSPs. The Thl-to-Th2 shifts generate antibodies against HSP65 that potentially attack arteries through antigenic mimicry. Although the development of the Thl cells mediates resistance to tuberculosis, it remains unclear whether HSP65-specific Thl responses are also pro-atherogenic. Our goals are to understand the respective atherogenic roles of HSP65-specific Thl and Th2 responses as well as the mechanism of the shifts. We will employ hypercholesterolemic apolipoprotein E-knockout (apoE-KO) mice and wild type (WT) controls immunized with HSP65 or heat-killed (HK) M. bovis BCG containing HSP65. We hypothesize that HSP65-specific Th2 responses will enhance atherogenic lesion development in apoE-KO mice. We will determine if immunization with HSP65 and chitin, a Thl adjuvant, or alum, a Th2 adjuvant, will have an effect on atherogenic lesion development in apoE-KO mice. We will further determine if adoptive transfer of HSP65- specific Thl cells or Th2 cells will have an effect on atherogenic lesion development in apoE-KO recipients. Treatment of mice with 89Sr destroys PGE2-MQ precursors in the bone marrow and suppresses the formation of splenic PGE2-MG. We hypothesize that this will also result in retention of the Thl responses without a shift to a Th2 response. Mice treated with 89Srwill receive HK-BCG immunization to determine the effect on response to HSP65. Finally, we will determine if transfusion of fit-1 +marrow cells from HK-BCG treated WT donors will restore the Thl-to-Th2 shifts in 89Sr-treated WT recipients.
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