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Influence of genetic and pharmacological factors on innate immunity and immune response in the development of post-transplant arteriosclerosis

14th national competition for scientific and technical research

Cellular and molecular mechanisms of atherosclerosis

Senior Researcher : José María Morales Cerdán

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Research Centre or Institution : Hospital Universitario 2 de Octubre. Madrid.


Cardiovascular diseases are the main cause of mortality in European countries. Nearly all of these pathologies are secondary to arteriosclerosis, a chronic inflammatory process of the arteries that produces an increase in arterial wall thickness with the consequent narrowing of the vessel, which implies a decrease in blood flow in tissues irrigated by the affected artery. At present, although the causes of arteriosclerosis are unknown, it is considered an inflammatory disease that originates from an aggression on the endothelium: the thin layer of cells that lines the interior of the arteries.

Although its causes are unknown, we are aware of the existence of several risk factors involved in the development of the disease, mainly tobacco, high blood pressure, infections, diabetes and other metabolic diseases.

The disease starts with the recruitment of a group of immune system cells to the initial area of damage. These cells devour fat particles while inducing the proliferation of other cells and the deposit of fibrous material on the arterial wall, thereby forming the "atheroma plaque" responsible for obstructing blood flow. Arteriosclerotic damage depends primarily on cellular immunity through the co-ordination of collaborating type 1 (Th1) T lymphocytes, while the role of humoral immunity is more controversial.

While there is no unanimity regarding the origin of immune system activation, there are two relevant hypotheses in this respect: infection and self-immunity, although an increasing number of authors consider that both are correct and that it is a mixed disease: a self-immune response that appears after an infection. Although the main micro-organisms that could cause this process, chlamydia pneumoniae, helicobacter pylori, cytomegalovirus and adenovirus, have been indirectly involved, these have not been proven, in animal models, to produce the disease.

The self-immunity hypothesis is endorsed by the observation, in animal models, that the immune reply against a protein (HP65) is involved in the creation of the spongy cells responsible for the onset of the damage.

Post-Transplant Arteriosclerosis (PTA)

A special form of arteriosclerosis that takes place in the arterial tree of transplanted organs, clinically termed chronic transplant rejection or graft vasculopathology. This arteriopathology develops rapidly and can be detected in most solid organ transplants in which hyperacute and acute rejection mechanisms are perfectly controlled. It has a very high incidence level: five years after the transplant, it appears in 50% of kidney or heart transplants, in over 70% of lung transplants and approximately 25% of liver transplants, currently representing a major health problem due to being the main cause of malfunction and loss of transplanted organs.

Although the short-term results of kidney transplants have improved dramatically in recent years (with a graft survival rate of 95% after one year), long-term results have only improved moderately due to two fundamental problems: transplant vasculopathology and death of the patient with a viable transplant, generally due to cardiovascular causes.

It seems paradoxical, and represents a major scientific challenge, that despite the importance of the role of immune cells in the origin of this type of pathologies, post-transplant arteriosclerosis (PTA) develops in patients receiving treatment with strong immunosuppressive drugs, such as calcineurin inhibitors, with a proven capacity to block the development of arteriosclerosis and proliferation of smooth muscle cells. However, not only does arteriosclerosis appear in these patients, but it does so in a much faster and intense way in the transplanted organ than in the rest of the vascular tree.

The characteristic post-transplant damage caused by arteriosclerosis is the concentric proliferation of smooth muscle cells in the innermost layer of the artery: the intimate layer, resulting in the development of a vessel-occluding layer: the neo-intimate layer, formed by concentric layers of smooth muscle cells, and endothelial and perivascular focal inflammation. The main difference between these types of damage and those caused by common arteriosclerosis is that, in the case of post-transplant, they are concentric in the affected area, while in the case of common arteriosclerosis, they are normally focal and excentric, located in high-pressure areas that receive blood flow directly, such as arterial bifurcations.

A particularly interesting case which represents a real scientific challenge is that of the few patients who do not suffer transplant vasculopathology and maintain the vascular tree of the graft in perfect condition for twenty or more years after the transplant, even in a better state than that of the rest of their vascular system. Among the kidney transplant patients controlled in our hospital, more than fifty still have viable grafts twenty (or more) years after the transplant, most of whom maintain normal renal function.

The factors that prevent the appearance of PTA in these patients are unclear, in which donor-receptor HLA incompatibility percentages are similar to those of other transplant patients. Some factors only partially justify this excellent progress: absence of acute rejection, low immunological risk and age. The study of the genetic and immunological peculiarities of this group represents a magnificent opportunity to understand the causes that makes it resistant to the development of vasculopathologies. The information obtained from the study of these patients enables us to extrapolate it to other transplant patients, thereby enabling the application of therapeutic actions aimed at preventing the appearance of vasculopathologies.

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