Granting Immunity
David Rawlings is developing gene therapy to treat primary immunodeficiency.
For most kids, a cold means a few days of misery and chicken-soup therapy. But a child with immune deficiencies could die of such a common infection.
Children's physicians are in the forefront of finding out how the immune system works...and how to fix it when things go wrong.
Hayley Ralph seemed to be a perfectly healthy little girl when she was born 5 years ago. Her parents, Angie and Chris Ralph, say that the first two years of Hayley's life were uneventful as far as her health was concerned.
Angie went back to work when Hayley was around 2 and enrolled her in day care and preschool. The toddler began to have serious infections in her ears and elsewhere. The Ralphs and their family pediatrician chalked it up to her new exposure to other children, and didn't think much of it.
But last year, Hayley's knee swelled. The pediatrician could not define the cause and referred the family to the Rheumatology Clinic at Children's. Cortisone injections brought the swelling down some, but within a month Hayley's gums were swollen, too, and bleeding.
Something was going on.
Primary immunodeficiency
Hayley spent last Labor Day weekend at Children’s for intravenous antibiotics. While she was at the hospital, blood tests revealed something startling: she had a form of primary immunodeficiency (PI) called hyper IgM, that is almost never seen in girls.
A patient with an immune deficiency is unable to muster the forces to fight off foreign substances such as bacteria, viruses, parasites, fungi, malignant cells, allergens and toxins. There are three kinds of immune deficiency: acquired, secondary and primary.
Acquired immune deficiency (AIDS) is caused by the HIV virus, which is contagious, explains Dr. Hans Ochs, professor of Pediatrics at Children’s and the University of Washington. Secondary immune deficiency can be caused by chemotherapy or childhood malnutrition. In contrast, primary immunodeficiencies, like Hayley’s, are genetic — people inherit them. PIs aren’t contagious, but can be passed on from parent to child.
The white blood cells we are born with give some innate immunity to disease. Our bodies learn other responses by using T cells and B cells, which originate in the thymus and bone cells, respectively.
T cells directly attack viruses and fungi and help regulate the immune system, while B cells make antibodies. When the body can’t make these cells or when they don’t work properly, infections can be overwhelming. In Hayley’s case, for example, there’s a communication problem between T and B cells.
“Hayley has T and B cells, but they don’t ‘talk’ to each other,” explains Dr. David Rawlings, head of Children’s Immunology Section and associate professor of Pediatrics and Immunology at the University of Washington.
Hayley Ralph with lifeguard / swim instructor Annie Baurichter.
“Usually, T cells tell the B cells which antibodies to make, what we call IgM or IgG. Hayley’s immune system makes plenty of IgM antibodies, but not IgG, which work better.
She can respond initially to infections, but the response isn’t strong enough or sustained, so what would be minor infections in other children were severe for her.”
By “severe,” Dr. Rawlings doesn’t mean “a really bad” cold or ear infection. It’s far more serious than that. Without the ability to fight bacteria and viruses, the body succumbs to them. Before the advent of antibiotics, most children with immune deficiencies died in the first few years of life.
But antibiotics aren’t the ultimate answer. They may control today’s infection, but what about tomorrow’s?
A new medical science
Immune deficiency first appeared in medical literature in 1952, when a researcher named Ogden Bruton analyzed the blood of a patient with frequent infections and found no antibodies. Dr. Ochs says that it took until the early 1970s for physicians to relate specific medical conditions to the immune system, and even then there wasn’t much they could do about them. Children continued to die of infections.
About 20 years ago, doctors developed a way to prevent infections by replacing antibodies via infusions of gamma globulin, a component of blood serum that’s high in disease-fighting ability.
Gamma globulin from many donors is pooled and administered intravenously, giving the patient the IgG antibodies he or she needs. It’s a control measure, not a cure; patients like Hayley need infusions their entire lives. (Hayley visits Children’s every three weeks for an infusion. Since beginning the regimen in 2001, she hasn’t been sick a single day.)
By the late 1980s and into the 90s, researchers such as Dr. Ochs and Dr. Rawlings were making the connection between immune deficiencies and genes, which opened up new possibilities for treatment.
Among the new treatments is gene therapy. It’s a bit more complicated than chicken soup. It involves bone-marrow transplants.
We usually associate bone-marrow transplants with cancer treatment, but in the last three years, doctors have been treating immune deficiencies with a special type of transplant. The major difference is that the patient is the donor.
Dr. Rawlings explains that bone-marrow cells are taken from the patient and infected with a virus that contains a normal copy of the defective gene. They then are returned to the patient. As the replaced bone-marrow cells divide, their daughter cells also carry a copy of the normal gene. These new normal cells have a growth advantage and reproduce better than cells without the normal gene.
A group of French physicians were the first to use this approach. Ten of the 11 patients treated were almost completely cured, but unfortunately two of these patients also developed leukemia several years later.
“Physicians here have some good ideas about how to avoid that problem and make the viruses safer,” says Dr. Rawlings. “It’s an important area of our research.”
Children’s leads in research
Dr. Hans Ochs has been researching immunodeficiency for over 30 years.
Other areas of research are identifying the specific gene responsible for a specific immune deficiency disease, developing new diagnostic techniques, and finding ways to treat immune deficiencies. Children’s is one of a handful of hospitals in the country researching and treating PI.
“Primary immune diseases begin in childhood,” Dr. Rawlings says, “which means Children’s sees a lot of these kids. As a result, we have developed an expertise no one else in the region has and we have become the referral center for children and adults with immune problems.
We have genetic testing capabilities no one else has. We serve as an international center for prenatal and neonatal testing, and for testing of adults to identify carriers of immune deficiency disorders.”
In fact, says Dr. Ochs, about 60 percent of the people the PI clinic sees are adults. “Many of these individuals would have died in childhood if it weren’t for antibiotics and other treatments for infection,” he comments.
Identifying carriers of PI is difficult, however. The science of immunology is relatively new, so families can’t trace with certainty any evidence of genetic predisposition for PI more than a generation or two back. Many children died of undiagnosed PI-related diseases when they were 2 or 3 years old, which complicates the problem.
And some PI-causing genes are recessive (both parents have to have them to pass the problem on to their children) while others are dominant (one parent alone can pass the gene on to the child). The situation is further muddied by spontaneous genetic mutations that occur in the egg or sperm prior to conception.
However, Dr. Ochs emphasizes that it’s important to know the family’s medical history.
“If a woman had a male sibling or other close male relatives who died prematurely of an infection or has other children with immune deficiencies, I’d recommend prenatal testing. Not only can we then take appropriate measures right after the baby is born, but some PI diseases are associated with a tendency to bleed. The obstetrician may recommend a Caesarean section to prevent damage to the baby.”
Far-reaching implications
“What we’re learning from our investigations of PI helps us understand a host of other diseases,” says Dr. Ochs. “The immune system is central to maintaining health. If it overreacts, we have autoimmune diseases such as lupus or arthritis. If it under-reacts, we can’t fight everyday infections, such as colds or the flu, or more serious conditions such as cancer.”
For example, Dr Rawlings and colleagues have discovered that if they breed a mouse with lupus with one that can’t make normal B cells, the offspring don’t develop lupus. This could lead to a drug that would control the disease in people.
Their research into PI also showed that an important cell-survival signal is greatly amplified in the most common form of adult lymphoma (cancer of the lymph system). “If we can inhibit that signal, we can block the survival of the cancer cells and potentially cure the disease,” says Dr. Rawlings.
One thing doctors don’t yet understand is the genetic basis of Hayley’s condition, but there are some clues, so they continue to study and search for a cure. What they learn may help others with the same syndrome.
“Hyper IgM occurs in one out of every 50,000 people,” he says, ”and most of them are boys. In the last five years, researchers have discovered five genetic causes, but in about 25 percent of children with this form of PI we haven’t yet discovered the defect. Hayley may point us in the right direction.”