**8. Conclusion**

Another promising area for further research is the development of tolerogenic vaccines for immune-mediated diseases (figure 7). Both foreign and self-antigens can be targets of tolero‐ genic processes. DCs can be converted to 'tolerogenic DCs' by addition of various immuno‐ modulating agents, including IL-10, transforming growth factor-beta (TGF-β) and 1,25 dihydroxyvitamin D3 [8], or they can be generated by using small interfering RNA (siRNA) that specifically targets IL-12p35 gene [112] (figure 7). Tolerogenic DC-based immunothera‐ py has recently been tested in mice as a possible novel approach to induce immunological tolerance for prevention or treatment of atherosclerosis [110]. Hermansson et al. [110] used IL-10 to induce tolerogenic DCs. Another group showed that oral administration of calci‐ triol, the active form of vitamin D3, induced the generation of tolerogenic DCs as well as a

of ApoE-/- mice, which resulted in an inhibition of atherosclerosis [113]. This was associated with increased IL-10 and decreased IL-12 mRNA expression. Furthermore, DCs from the calcitriol group showed reduced CD80 and CD86 expression and decreased proliferative ac‐ tivity of T lymphocytes, indicating that tolerogenic or maturation-resistant DCs show some similarities with immature DCs [113]. Hussain and colleagues [114] hypothesized that aspir‐

tion in experimental models of autoimmune atherosclerosis. Aspirin-induced tolerogenic DCs initiated regulatory activity in responder T cells as they showed a decreased expression of costimulatory molecules and an increased expression of immunoglobulin-like transcript 3 (ILT-3), which is a co-inhibitor of T cell activation required to induce Tregs [114,115,116]. In‐ deed, the presentation of antigen complexes to T cells in the absence of costimulatory signals could lead to anergy or apoptosis of T cells, or the induction of Treg. Therefore, it might also be useful to adjust the expression of costimulatory molecules on pulsed DCs *ex vivo* prior to

**Figure 7.** Generation of tolerogenic DCs to develop tolerogenic vaccines. Tolerogenic DC-based immunotherapy has recently been successfully tested in mice as a possible novel approach to induce immunological tolerance for preven‐

A completely different strategy that might be used in therapeutic intervention implicates the use of DCs to deplete specific immune cells, such as the detrimental Th1 or Th17 cells, in atherosclerosis. The opposite approach has been shown to work in a mouse model of athero‐

in may also induce tolerogenic DCs and CD4+ CD25+ FoxP3+

Tregs in the lymph nodes, spleen, and atherosclerotic lesions

Treg cells activity/augmenta‐

significant increase in Foxp3+

70 Current Trends in Atherogenesis

the vaccination [96,98,97,94,117,118].

tion or treatment of atherosclerosis.

As it is now well accepted that atherosclerosis is an immune-mediated disease, the target‐ ing of its cellular components might open possibilities for new therapeutic strategies to at‐ tenuate the progression of the disease. DCs seem to initiate and regulate immune responses in atherosclerosis and they are also involved in controlling cholesterol homeo‐ stasis by yet unknown mechanisms. It would be important to identify the pathway(s) through which CD11c+ cells may modulate the levels of plasma cholesterol. One should take into account that DCs represent a very heterogeneous population, with many subsets that have different phenotypes, functions, origin and anatomical distribution. So far, it is unclear if all DCs have equal antigen-presenting capacities, and very little is known about a preferential DC subset that is responsible for T cell-induced inflammation in the vessel wall. Moreover, there is a close relationship between DCs and macrophages, and the dis‐ tinction between both cell types is even further complicated by their plasticity. Future studies are essential to determine which DC subtypes exert pro- or anti-atherogenic ef‐ fects. It is crucial to understand the diversity in DC subsets to target DCs for immunomo‐ dulation therapies. Furthermore, functional differences between phenotypically similar mouse and human DC subtypes should also be studied. Nevertheless, DC-based vaccina‐ tion strategies have been proven successful and animal studies provide some promising data for the treatment of atherosclerosis as well. Yet, several issues, such as the most ap‐ propriate antigen(s) for loading DCs and the optimal type of DC used for vaccination re‐ main to be further investigated.

## **Acknowledgements**

This work was supported by the University of Antwerp [GOA-BOF 2407 and TOP-GOA 3018].

[9] Rossi M and Young JW. Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol 2005;175(3) 1373-1381.

Dendritic Cells in Atherogenesis: From Immune Shapers to Therapeutic Targets

http://dx.doi.org/10.5772/52900

73

[10] Rezzani R, Rodella L, Zauli G et al. Mouse peritoneal cells as a reservoir of late den‐

[11] Bobryshev YV and Lord RS. Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta. Arch Histol Cy‐

[12] Niessner A and Weyand CM. Dendritic cells in atherosclerotic disease. Clin Immunol

[13] Milioti N, Bermudez-Fajardo A, Penichet ML et al. Antigen-induced immunomodu‐ lation in the pathogenesis of atherosclerosis. Clin Dev Immunol 2008;2008(723539-

[14] Perrin-Cocon L, Coutant F, Agaugue S et al. Oxidized low-density lipoprotein pro‐ motes mature dendritic cell transition from differentiating monocyte. J Immunol

[15] Alderman CJ, Bunyard PR, Chain BM et al. Effects of oxidised low density lipopro‐ tein on dendritic cells: a possible immunoregulatory component of the atherogenic

[16] Zaguri R, Verbovetski I, Atallah M et al. 'Danger' effect of low-density lipoprotein (LDL) and oxidized LDL on human immature dendritic cells. Clin Exp Immunol

[17] Nickel T, Schmauss D, Hanssen H et al. oxLDL uptake by dendritic cells induces up‐ regulation of scavenger-receptors, maturation and differentiation. Atherosclerosis

[18] Profumo E, Buttari B, and Rigano R. Oxidative stress in cardiovascular inflammation: its involvement in autoimmune responses. Int J Inflam 2011;2011(295705-

[19] George J, Harats D, Gilburd B et al. Adoptive transfer of beta(2)-glycoprotein I-reac‐ tive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Cir‐

[20] Buttari B, Profumo E, Mattei V et al. Oxidized beta2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response. Blood

[21] Buttari B, Profumo E, Capozzi A et al. Advanced glycation end products of human beta(2) glycoprotein I modulate the maturation and function of DCs. Blood

[22] Wick G, Knoflach M, and Xu Q. Autoimmune and inflammatory mechanisms in

atherosclerosis. Annu Rev Immunol 2004;22(361-403.

dritic cell progenitors. Br J Haematol 1999;104(1) 111-118.

micro-environment? Cardiovasc Res 2002;55(4) 806-819.

tol 1995;58(3) 307-322.

2001;167(7) 3785-3791.

2007;149(3) 543-552.

2009;205(2) 442-450.

culation 2000;102(15) 1822-1827.

2005;106(12) 3880-3887.

2011;117(23) 6152-6161.

2010;134(1) 25-32.
