Conclusions Future investigations and therapeutic potential

Innate immunity represents an attractive source of therapeutic targets because it is linked directly to development of atherosclerosis, and also because of its strategic position in controlling inflammation, autoimmunity, and antibody responses. Lig-ands for specific TLRs are already being developed and evaluated in clinical trials as vaccines or adjuvants [93, 94]. Innate immune cells, particularly DCs, are being evaluated for possible roles in delivering antigen and inducing antitumor immunity [95] and in controlling autoimmunity [96]. Therapies aimed at tipping the Th1/Th2 balance toward a Th2 response may be a fruitful area of investigation; among these are molecules that target specific aspects of TLR signaling [93]. NK cells and NK T cells may be useful in treating cancer [97], and since both have been recently linked to atherosclerosis [98, 99], the possibility arises that cellular therapy utilizing these lineages might also prove useful in atherosclerosis. Although still in early development, therapeutic utilization of T regulatory cells in diseases such as type 1 diabetes is promising [100] and could be explored for treating atherosclerosis as well. Since TLR signaling has been implicated in neointimal proliferation after arterial injury [78], myocardial reperfusion injury [101], heart failure [102], and unfavorable ventricular remodeling after myocardial infarction [103], the potential utility of TLR inhibitors in drug-eluting stents and in acute coronary syndromes is being explored.

Thus, intensive investigation of a number of diseases is increasingly directed toward therapeutic manipulations of various aspects of innate immunity, and similar approaches in atherosclerosis warrant development. Manipulating innate immunity in ways that limit or even prevent atherosclerotic plaque development and destabilization carries the risk or compromising host defense. A major challenge to future translational investigations will be to achieve the goal of limiting pro-athero-genic innate immune influences while simultaneously maintaining adequate and appropriate innate immune defense mechanisms. Continued rapid progress in our understanding of how TLR signaling works and particularly how it is involved in vascular disease can be expected to enable us to one day achieve these goals in a way that could dramatically limit the two major threats to global wellbeing - cardiovascular disease and infection.

Acknowledgments

This work was supported by grants from the NIH (HL 66436 and AI 058128 to M.A.). Generous support was also provided by the Mirisch Foundation, United Hostesses Charities, the Eisner Foundation, the Grand Foundation, the Ornest Fam-

ily Foundation, the Entertainment Industry Foundation, and the Heart Fund at

Cedars-Sinai Medical Center, Los Angeles, California.

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