Fight Aging!

Atherosclerosis is a universal age-related condition in which fatty plaques grow in blood vessel walls, eventually rupturing to produce a heart attack or stroke. Even prior to that, reduced blood flow due to narrowed arteries contributes to heart failure and numerous other age-related conditions. The chronic inflammation that accompanies aging is a contributing factor in the development of atherosclerosis, but efforts to suppress inflammation have so far produced results that are only in the same ballpark as the effects of statins and similar approaches to lower LDL cholesterol in the bloodstream. This is to say a modest slowing of atherosclerosis, but no great reversal of existing plaque.

This may be the case because present anti-inflammatory strategies are relatively crude, while inflammatory signaling is a complex process spanning hundreds to thousands of proteins and other molecules inside cells and passing between cells of many different types and function. Or it could be because targeting the state of inflammation isn't the most effective way forward. It seems like a compelling target, however, given that the progression of atherosclerosis, the formation of fatty plaques, comes down to the dysfunction of macrophage cells. It is macrophages of the innate immune system that are responsible for clearing cholesterol from blood vessel walls, and inflammatory signaling can (a) cause macrophages to focus instead on other tasks, making them less effective when it comes to cholesterol clearance, and (b) attract more macrophages to existing plaque environments. Large plaques are packed with a toxic mix of cholesterol and altered cholesterols that is capable of overwhelming and killing even larger than usual numbers of macrophages, adding their mass to the plaque.

In today's open access paper, researchers discuss a more sophisticated approach to suppression of inflammation, employing regulatory T cells that are normally responsible for resolving inflammation after its purpose is complete. Using cells in principle allows the full spectrum of inflammation resolving mechanisms to be employed, even those that are poorly understood at the present time. On the other hand, using cells introduces a great deal of complexity and cost into any potential therapy. Cell therapies that work in animal studies in the academic environment remain very challenging to develop into a reliable treatment that will satisfy regulators, and the same goes for attempts manipulate the immune system in this way.

Regulatory T Cells in Atherosclerosis: Is Adoptive Cell Therapy Possible?

Atherosclerosis is an insidious vascular disease with an asymptomatic debut and development over decades. The aetiology and pathogenesis of atherosclerosis are not completely clear. However, chronic inflammation and autoimmune reactions play a significant role in the natural course of atherosclerosis. The pathogenesis of atherosclerosis involves damage to the intima, immune cell recruitment and infiltration of cells such as monocytes/macrophages, neutrophils, and lymphocytes into the inner layer of vessel walls, and the accumulation of lipids, leading to vascular inflammation. The recruited immune cells mainly have a pro-atherogenic effect, whereas CD4+ regulatory T (Treg) cells are another heterogeneous group of cells with opposite functions that suppress the pathogenic immune responses. Present in low numbers in atherosclerotic plaques, Tregs serve a protective role, maintaining immune homeostasis and tolerance by suppressing pro-inflammatory immune cell subsets.

The development of atherosclerosis and the stability of atherosclerotic plaques are directly related to changes in the balance of the effector and suppressor populations of the immune system. Treg cells are key immunocytes that control immune responses and maintain tissue homeostasis. Therefore, manipulations aimed at regulating Treg cells are of interest for considering the development of personalised treatments for atherosclerosis. There are several general approaches to modulating Treg activity and Treg numbers in atherosclerosis, but promising preclinical and several clinical studies have suggested that adoptive Treg transfer may be a treatment option for atherosclerosis. For therapies based on adoptive cell transfer, two kinds of Treg cells can be used: polyclonally expanded Treg cells or antigen-specific Treg cells.

In early and ongoing studies of Treg-based adoptive therapies, a general ineffective approach is used: peripheral Treg cells are sorted, polyclonally expanded ex vivo, and infused in certain quantities into the bloodstream. However, this approach does not take into account a number of key factors. First, this approach ignores the functional state of Treg cells. Currently, Treg cells are isolated from peripheral blood mononuclear cells (PBMCs) and expanded ex vivo. Treg cells isolated from PBMCs are heterogeneous and largely represented by cells with induced FOXP3 expression. The lack of potent and stable FOXP3 expression and steady suppressive activity are the common problems in this approach to cell therapy. Second, it is important to increase the specificity of Treg-based adoptive therapy. Antigen-specific Treg cells have been shown to be more powerful in suppressing alloimmune responses in vitro and in vivo compared to polyclonally expanded Treg cells. Thereby, infusions of polyclonally expanded Treg cells with unknown antigen specificity cannot effectively inhibit the target cells and suppress undesirable immune responses and can lead to unwanted side effects.

Recently, new highly effective therapeutic approaches based on adoptive therapy with genetically engineered Treg cells have emerged, which can overcome the barriers to the use of Treg cells for immunotherapy of atherosclerosis and other immune-inflammatory diseases. These approaches include the application of cells with genetically modified T-cell receptors or with the expression of highly specific chimeric antigen receptors (CARs), as well as the use of genome editing techniques such as CRISPR/Cas9. CAR technology is a very promising tool, allowing T cells to be reprogrammed to overcome the limitations of native T cells. CAR-modified T cells have already been successfully applied for the treatment of certain types of cancer. Therefore, this technology can also be effective in the case of Treg cells.

In conclusion, a number of studies have shown that CD4+ Treg cells are crucial in the maintenance of peripheral tolerance and have an important role in the control of atherosclerosis-related inflammation. Therefore, Treg cells are a promising target of major research efforts focused on immune-modulating therapies against atherosclerosis. Developing anti-atherosclerotic Treg-based therapies faces challenges. However, rapid progress in genetic, epigenetic, and molecular aspects of cellular immunology gives hope for a fast-track solution.