By William J. Cromie

Gazette Staff

Vicki and Fred Modell's dream came true last week. They gave $1 million to Children's Hospital and Raif Geha, Prince Turki bin Abdul Aziz Al-Saud Professor of Pediatrics at the Medical School.

In 1986, their son, Jeffrey Modell, then 15, died from a primary immune deficiency, one of a group of diseases that affect an estimated 500,000 children in the United States.

"After Jeffrey's death, we decided to raise what we thought would be a modest sum of money in his name," Fred Modell, a New York City businessman, said. "We had hoped to raise about $3,000, but the response was so overwhelming that, before we knew it, we had collected $300,000 and established the Jeffrey Modell Foundation. Our mission is to support research and to help parents find the latest treatments for this little-known but deadly disease. It's a dream come true to be able to support Dr. Raif Geha and his colleagues, who are doing some of the most exciting work in primary immune deficiency in the country."

Children suffering from this malady lack one or more factors needed to fight off everyday infections. They suffer symptoms that range from recurrent colds and chest infections to lethal pneumonia and cancer.

The best-known examples are so-called "bubble babies," who must live in sterile shelters to protect them from direct contact with everyone, including their parents. Fortunately, such cases are rare.

"Seventy different immune deficiency diseases have been identified, and we are sure there are many more that we don't know about," Geha notes. "Our goal is to find what factor is missing in each disease and to provide a substitute when possible. The generous gift provided by the Modells will help us do this."

Confused with AIDS

Most cases can be treated with regular injections of missing immune-system ingredients called immunoglobulins, taken along with antibiotics. Such treatment sustains Joseph Graziano, 5, who was diagnosed with an immune disorder at five months of age. His father and mother attended the dedication of the Jeffrey Modell Laboratory at Children's Hospital on Oct. 8.

"Because Joe needs to be careful about exposure to other children with common childhood illnesses such as chickenpox, we considered not sending him to school this year," says his father, Stan. "But because he's an active and social child, we decided the benefits of interacting with other kids outweigh the risks."

"At this point," comments his mother, Nancy, "Joe thinks everyone gets infusions of immunoglobulin or takes antibiotics like he does."

Children with immune deficiencies have a high risk of contracting pneumocystis pneumonia, which is life-threatening only to people with impaired resistance to infection. Jeffrey Modell died from this opportunistic disease.

Pneumocystis pneumonia also kills many people with AIDS because their immune systems are weakened by the human immunodeficiency virus (HIV). When Joe Graziano was diagnosed with it, doctors concluded that he was infected by HIV that he got from his parents.

"We were shocked," his father recalls. "We had to wait for what turned out to be an extremely long weekend before we could be tested and find out, with great relief, that the doctors were wrong."

Replacing What's Missing

The genetic condition that killed Jeffrey Modell is inherited from a child's mother and affects only boys. Daughters of these women will be free of the disease, but half of them will carry the mutation, which they can pass to their children. Half of the boys will inherit the disease.

Nancy Graziano expects her second child in November, a boy. When asked how he felt about the 50-50 risk of his son being born with primary immune deficiency, Stan said, "we're hopeful that he will be free of it."

The most serious forms of this illness come from a deficiency of T-cells, the same white blood cells that are ravaged by AIDS. T-cells recognize viruses, bacteria, and the microbe that causes pneumocystis pneumonia. They bind molecules from these organisms with so-called B cells, which then produce immunoglobulins to neutralize the invaders.

"In kids with B-cell deficiencies, we provide, via injection, those immunoglobulins not being made by the immune system," Geha explains. "The immunoglobulins are extracted from the blood plasma of normal people. With T-cell deficiencies you often have to perform bone marrow transplants to enable a patient to produce the missing protective components. Treating B-cell deficiencies is like putting fuel in a car with an empty gas tank; with T-cell problems you must replace the entire engine."

About 5 percent of primary immune deficiencies in this country, representing some 25,000 children, stem from a lack of T-cells. In nations where consanguineous marriages are legal, the incidence is much higher.

"If a child has no immune system at all, he or she will either die or be cured by a bone marrow transplant," Geha says. If some T-cells exist, the situation becomes complex because these cells can cause transplant rejection.

"If you are forced to wait for the right donor, the child may die in the meantime," Geha continues. "If you go ahead with a match that's less than ideal, the child's chances of surviving are not good. It's a terrible Catch-22 situation."

The best way to treat these serious deficiencies would be to replace any defective genes. However, those genes must first be identified.

"Rapid progress in this area is being made by using knockout technology," Geha notes. "We knock out or eliminate specific genes from mice, and look for the same kinds of immune deficiencies we see in humans."

To date, replacing defective genes in humans has not produced the magic cures researchers once believed it would. It is extremely difficult to get the replacement gene to the right place and to turn it on or off as needed.

"Like anything new, gene therapy involves many problems yet to be worked out," Geha admits. "But I have no doubt it will happen in the next decade or two. The $1 million we have received from the Modell Foundation will help us to identify gene defects that are candidates for gene therapy."

The professorship held by Geha was named for another benefactor, a brother of King Fahd, the reigning monarch of Saudi Arabia. Geha, who is Lebanese, treated the son of Prince Turki bin Abdul Aziz Al-Saudi for what he calls "a mild immune deficiency." Pleased with the result, the prince asked what he could do for the doctor.

Geha, who was tenured at the time, replied, "Nothing for me, but you can do something for the [Harvard] Medical School and to perpetuate the name of your family." The chair was endowed in 1991.