CLINICAL TARGETS
INFLAMMATION
Inflammation is a normal response of the body to protect tissues from infection, injury or disease. The inflammatory response begins with the production and release of chemical agents by cells in the infected, injured or diseased tissue. These agents cause redness, swelling, pain, heat and loss of function. Inflamed tissues generate additional signals that recruit leukocytes to the site of inflammation. Leukocytes destroy any infective or injurious agent, and remove cellular debris from damaged tissue. This inflammatory response usually promotes healing but, if uncontrolled, may become harmful.
The inflammatory response can be either acute or chronic. Acute inflammation typically lasts only a few days. The treatment of acute inflammation, where therapy includes the administration of aspirin and other non-steroidal anti-inflammatory agents, provides relief of pain and fever for patients. In contrast, chronic inflammation lasts weeks, months or even indefinitely and causes tissue damage.
CHRONIC INFLAMMATION
In chronic inflammation, the inflammation becomes the problem rather than the solution to infection, injury or disease. Chronically inflamed tissues continue to generate signals that attract leukocytes from the bloodstream. When leukocytes migrate from the bloodstream into the tissue they amplify the inflammatory response. This chronic inflammatory response can break down healthy tissue in a misdirected attempt at repair and healing. Diseases characterized by chronic inflammation include, among others:
- Diabetes
- Coronary artery disease (atherosclerosis);
- Rheumatoid arthritis;
- Asthma;
- Solid organ transplant rejection.
Diabetes
- Diabetes is a chronic condition that arises when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin produced.;
- Insulin is a hormone made by the pancreas that helps ‘sugar’ (glucose) to leave the blood and enter the cells of the body to be used as ‘fuel’. When a person has diabetes, either their pancreas does not produce the insulin they need (type 1 diabetes) or additionally the body cannot make effective use of the insulin they produce (type 2 diabetes).;
- Diabetes is the fourth leading cause of death in most developed countries.;
- Each year, over three million deaths worldwide are attributable to diabetes-related causes.
Type 1 diabetes is an autoimmune disease that prevents the body from producing insulin. Type 1 diabetes occurs most often
in children and young adults. Approximately 5 to 10 percent of people with diabetes have type 1 diabetes.
Type 2 diabetes is a metabolic disorder that results from a combination of the body’s inability to make effective use of
the insulin produced, and steadily worsening production of insulin to overcome that effect. Genetics, obesity, inappropriate diet and
lack of physical activity are factors that appear to play a role in the development of type 2 diabetes.
Type 2 diabetes occurs most often in adults over the age of 40 years and accounts for up to 95% of all diabetes. However, as a consequence
of increased obesity and inactivity among the young, type 2 diabetes is now affecting children and young adults. The management of type 2
diabetes focuses on keeping blood glucose, blood pressure and blood fats at near-normal levels. Almost 50% of people with type 2 diabetes
are not aware that they have the disease.
Without proper insulin production and action, sugar remains in the blood, leading to chronic hyperglycaemia (raised blood glucose levels).
This can result in short and long-term complications, many of which, if not prevented and left untreated, can be fatal. Among the most
common long-term complications is cardiovascular disease. According to experts, the cardiovascular implications of diabetes are so severe
that it is equivalent to having already had a heart attack. People with diabetes are two to four times more likely to develop cardiovascular
disease than those without diabetes. Cardiovascular disease, including heart attack and stroke, ultimately kills two out of three people
with diabetes.
Atherosclerosis is the leading cause of morbidity and mortality in Western societies, claiming more lives each year than all forms of cancer combined. Coronary heart disease (CHD) is the most common, and serious, consequence of this disease.
Atherosclerosis is a common and progressive disease of the arteries that results from inflammation and the buildup of plaque under the inner
lining of arteries and swells into the hollow or lumen of the arteries. This accumulation takes place over years, even decades, developing
slowly and insidiously. Plaque formation begins as fatty streaks on the inner arterial wall. Over time the fat deposits accumulate and grow,
narrowing the opening of the artery. Surrounding smooth muscle tissue also proliferates to form larger plaques. The damage from
atherosclerosis occurs when the swelling, called a plaque, becomes large enough to reduce or completely block the blood flow through the
arteries. The artery wall becomes thickened and loses its elasticity. Any tissue supplied by the blocked artery is in danger. Risk factors
associated with atherosclerosis include: elevated cholesterol and triglyceride levels, high blood pressure, smoking, diabetes, obesity and
physical inactivity. Atherosclerosis, depending on the location of the artery it affects, may result in heart attack, stroke or amputation.
Evidence also suggests that insulin resistance, independent of other risk factors, could be a major determinant of atherosclerosis.
Atherosclerosis of the blood vessels of the heart is called coronary artery disease. There are no medications available for physicians to
treat directly the underlying chronic inflammation of atherosclerosis.
Transplant Rejection
Industry sources report there are over 150,000 organ transplant recipients in the United States who may be at risk of chronic transplant rejection. Except for transplants between identical twins, all transplant donors and recipients are immunologically incompatible. This biologic incompatibility is a barrier that causes the recipient’s immune system to try to destroy or reject the new organ, tissues or cells. The current treatment for prevention of organ transplant rejection focuses on the use of powerful immunosuppressive drugs such as cyclosporin A, tacrolimus, and rapamycin (sirolimus). These drugs, which are initiated during the acute rejection phase, need to be taken continuously after the transplant and often cause side effects, but still lead to long-term rejection of the transplant. Immunosuppressants may also impair the recipient’s immune system in order to reduce the immune response against the graft. According to the Scientific Registry of Transplant Recipients, even with the use of immunosuppressants, patients have approximately 20 to 50 percent risk of losing a donated organ during the first three years following transplantation, and less than 50 percent of patients have functioning grafts after approximately ten years. Accelerated inflammation of the graft blood vessels (arteritis) is a common cause of late (chronic) organ loss, which may be particularly appropriate for AGI-1096 therapy.
Graft survival rates decline sharply over time
www.niaid.nih.gov/publications/transplant/fig2
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