By David N. Leff
A favorite feature of the zillion cells inhabiting the human body is stickiness.
¿It¿s absolutely essential for certain cells to stick to things,¿ observed research pharmacologist Julia Brittain, at the University of North Carolina, Chapel Hill. ¿Otherwise,¿ she added, ¿you would not have a brain.¿ How come? ¿If there were no mechanisms by which neurons could attach to some sort of supportive matrix in your brain, you wouldn¿t have it. The same with your skin, your kidneys ¿ everything.¿
But too much cellular stickiness in the wrong places can be life threatening. Such is the case of a great many African-Americans in the U.S., afflicted with sickle cell disease (SCD). Some 13 percent of the U.S. population ¿ now 281.5 million by the 2000 census ¿ consists of blacks, of whom one in 625, Brittain said, suffers from SCD.
In this inherited ailment, a mutation affecting the hemoglobin cargo in the body¿s red blood cells causes those smooth, supple oval erythrocytes to shrivel into sickle-shaped, rigid cells that give the disease its name. ¿As a result of this mutation,¿ Brittain went on, ¿those sickle cells become stickier, and adhere to the inner walls of the blood vessels, thus presumably clogging blood flow.¿
Two proteins, thrombospondin (TSP) and integrin, make this adhesion happen.
¿You can think it¿s like Velcro lining your blood vessel,¿ Brittain suggested. ¿Every now and then thrombospondin, a vessel-wall protein, acts up. This is like one part of the Velcro closure. Integrin-associated protein [IAP], an adhesion molecule on the surface of sickle cells, is like the other part. So when TSP is exposed to the sickle cells, the two stick to each other ¿ just like Velcro attachments.¿
Brittain is first author of a paper in the April 1, 2001, issue of the twice-monthly journal Blood. Its title: ¿Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin.¿ In it, she and her co-authors report, ¿discovering in vitro that IAP is the other end of the Velcro ¿ the mechanism by which sickle cells may stick to the lining of blood vessels.¿
Non-Brain Ischemia Starves Tissues Of Oxygen
To which the paper¿s senior author, pharmacology professor Leslie Parise, made the added point: ¿IAP now becomes a potential new therapeutic target for preventing the cells from adhering to the vessels.¿
That adherence, gumming up an SCD patient¿s entire circulatory system, creates a sort of whole-body ischemia, which starves tissues and organs of the oxygen cut off by the intermittent damming up of the red blood cells.
This dire, unpredictable event, Brittain pointed out, ¿causes vaso-occlusive crisis, considered the hallmark of sickle cell disease.¿ The hallmark of the crises themselves is intense pain. ¿Most of the time,¿ she recounted, ¿the pain is localized in certain areas ¿ abdominal, leg, bone, kidneys, lungs.¿
Brittain pointed out that ¿SCD is a homozygous recessive disease. That means, in order to have the disease, you must harbor two copies of the mutated hemoglobin ¿ one copy from each parent. People carrying only a single mutant copy,¿ she continued, ¿are said to be heterozygous ¿ endowed with the sickle cell trait, but not the disease. About 8.6 percent of the black population are carriers. Like Mendelian smoking guns, one in four of their offspring is likely to inherit SCD.¿
Carriers are generally thought to be free of all symptoms, but ¿there is some controversy in the field about that,¿ Brittain said. ¿Clearly carriers do not have SCD, though they may manifest some problems as a result of the mutation, such as very mild anemia.¿
During embryonic gestation, the fetus subsists on a developmental hemoglobin. This is gradually replaced after the child is born, and downplays fetal hemoglobin in increasing favor of adult hemoglobin. It is this variant that gets mutated, and confers the disease. The mutation is a switch from one amino acid, glutamic acid, to another, valine.
Sickle cell disease is endemic in sub-Saharan Africa, which is a hotspot of malaria. ¿People who carry the sickle cell trait,¿ Brittain observed, ¿may be more resistant to malarial infection. But this is based largely on correlative data, so that link has not been made.
¿Infants who are homozygous for SCD, unless treated promptly, typically die by the age of 5,¿ she pointed out. ¿That¿s why the resistance is thought to be with the trait. It¿s apparently the carriers who are protected against malaria. But clearly there is some sort of selective evolutionary pressure to keep the trait in the population.
¿Death from SCD,¿ she continued, ¿can be due to anything. There is chronic impairment of blood flow in addition to the acute crisis events. So typically if a patient dies directly as a result of SCD, it¿s likely from end-organ failure, such as liver or kidney shutdown. Patients also die of cerebral stroke ¿ or sometimes they just die.¿ Life expectancy is less than 50 years.
Until lately, there has been no medical treatment for sickle cell sufferers. But very recently, a powerful anticancer drug, hydroxyurea, successfully passed extensive, controlled clinical trials to become the drug of choice for alleviating the symptoms of sickle cell disease.
¿Its exact mode of action seems to be a little in question,¿ Brittain commented. ¿Hydroxyurea does induce production of the fetal hemoglobin, and this is thought to diminish the effective amount of the mutated molecule. So with fewer abnormalities in the red cells, these hydroxyurea capsules can promote overall wellness in the patient. It works quite well for some, and is administered chronically.¿
Mouse Antibody Against Receptor Holds Promise
The co-authors are seeking to develop an SCD medication that will address the ailment¿s stickiness etiology. ¿We have potentially discovered an agent that may reduce the duration or severity of vaso-occlusive crisis in SCD,¿ Brittain told BioWorld Today. ¿It¿s a mouse monoclonal antibody against the human integrin-associated protein receptor, and does appear to disrupt the interaction of IAP with thrombospondin ¿ in vitro. We hope to try this blocker in mice,¿ she said, ¿but we have some pilot studies to do first.¿
She concluded: ¿We are still years away from taking this into the clinic, but we are one step closer than we were a year ago.¿