Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Abstract

In the United States, >200 000 new patients are diagnosed with abdominal aortic aneurysm (AAA) each year. Consequently, >40 000 highly morbid aortic reconstructions are performed each year to prevent aneurysm rupture, a catastrophic event associated with near-certain mortality. No pharmaceutical currently exists to slow aneurysm growth, but a 50% reduction in diameter growth per annum could halve the number of aortic reconstructions required. Therefore, successful use of cell therapy to modulate chronic inflammation hallmark to AAA to slow diameter expansion represents a potentially paradigmaltering treatment.There continues to be no US Food and Drug-approved medication to slow or stop AAA growth. This deficit is certainly not because of a lack of effort over the previous decades. Initial investigations focused on the reduction of mechanical stress through decreasing blood pressure and sac pressurization cycles; however, clinical trials investigating drugs, such as, angiotensin II-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, all failed to demonstrate a therapeutic reduction of diameter growth compared with placebo. Next, the inhibition of matrix metalloproteinases was trialed with doxycycline, an antibiotic inhibitor of matrix metalloproteinases 2 and 9. Doxycycline also treats species of Chlamydia, which were isolated from the aortic walls of a minority of aneurysmal arteries. Although initial uncontrolled results were promising, therapeutic response was not replicated in large randomized studies. Last, aortic wall inflammation was targeted using statins, a ubiquitous anti-inflammatory, lipid-lowering drug to limited success. The discovery of a nonsurgical treatment for AAA is contingent on the robust understanding of disease pathogenesis, which continues to be nebulous at best.AAA risk factors, such as, tobacco abuse, advancing age, uncontrolled hypertension, male sex, and white ethnicity, have all been well described but fail to provide evidence elucidating pathogenesis. Regardless, existing evidence implicates that disease initiation is multifactorial with a strong genetic element.There has been a focus of late toward the role of autoimmune mechanisms in AAA formation. The characterization of aortic wall inflammation consisting of mononuclear infiltrates, immunoglobulins, cytokines, and proteases implicate both a host innate and adaptive response. Of note, concentrations of CD4 + T cells have been recently discovered in the periadventitial vascular-associated lymphatic tissue expressing identical T cell receptors, against a currently unknown antigen, and therefore clonally expanded, providing crucial evidence for AAA as an autoimmune disease.1 Moreover, interleukin (IL)-17, a cytokine elaborated from the antigen-specific Th17 lymphocyte and overexpressed in autoimmune disorders, is highly expressed in the AAA condition. Abrogation of this cytokine, in animal models, has demonstrated efficacy in decreasing aneurysm diameter growth.2 Although several putative autoantigens have b...

Leukocyte subsets and abdominal aortic aneurysms detected by screening in men

“…Different classes of leukocytes may be involved in and/or modulate the development of AAA, as suggested by their infiltration in human advanced aneurysms [8]. Our finding of an association between circulating levels of leukocyte subsets and screening-detected AAA may support the hypothesis of an early and broad involvement of the immune system in the pathogenesis of AAA [8,13]. Alternatively, AAA-associated factors, such as activated endothelium and thrombus formation may trigger leukocytosis, which may or may not be involved in disease development.…”

“…For example, carriers of IL6R genetic variants that have been associated with AAA [21] may have a heightened response to interleukin-6 triggered by tobacco smoke [12]. AAA development has been suggested to have an autoimmune component, similar to atherogenesis [13,22], and autoimmune disorders such as rheumatoid arthritis are associated with a higher risk of AAA [23]. An interesting hypothesis is that smoking may trigger both formation of and autoimmune activation against elastin fragments from lung, in accordance with elevated elastin (auto-)antibodies in patients with AAA [13].…”

“…To date, smoking cessation is the only efficient way to reduce AAA growth; no medication has yet shown a proven effect on AAA disease development [8,13,26]. As large aneurysms unequivocally require surgery, any pharmaceutical intervention against AAA must be initiated when aneurysms are still small.…”

“…As large aneurysms unequivocally require surgery, any pharmaceutical intervention against AAA must be initiated when aneurysms are still small. Earlier studies have mainly focused on advanced disease, whilst studies derived from population-based AAA screening are better positioned to capture processes that take place earlier in the pathogenesis, and thereby still possible to target noninvasively [13,26]. Although the present study does not support neutrophil count, lymphocyte count, or the neutrophil-to-lymphocyte ratio as useful markers to predict presence of AAA in men, counts of white blood cells and their subtypes have been shown to predict the course of cardiovascular diseases [18,19].…”

Association between abdominal aortic aneurysms and alcohol-related diseases

“…No evidence has suggested that commonly used cardiovascular medications, including calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and statins, can effectively limit the progression of AAA. [ 29 ] The usual threshold for elective AAA repair is an aortic diameter of 5.5 cm in men and 5.0 cm in women. Repair should be considered for an AAA with a growth rate exceeding 0.5 cm in diameter over a period of 6 months, regardless of its absolute size.…”