This study will evaluate the safety and effectiveness of the drug, interferon gamma, in
treating leukocyte adhesion deficiency type I (LAD I). Patients with this inherited immune
disorder do not have enough proteins called adhesion molecules on their infection-fighting
white blood cells, impairing the ability of these cells to get to the site of infection. As
a result, patients have recurrent infections of soft tissues, such as the skin, gums and
gastrointestinal tract, and poor wound healing. Infants with severe LAD I often die from
multiple infections. Interferon gamma may increase the number of adhesion molecules on white
blood cells, and thus improve their function.
Patients with LAD I who weigh more than 13 kilograms (28.5 pounds) may be eligible for this
study. Candidates will have personal and family medical histories taken, a physical
examination, blood and urine tests and a chest X-ray or computed tomography (CT) scan.
Participants will receive injections of interferon gamma under the skin 3 times a week for 3
months. Adult patients will be taught how to give their own injections (similar to insulin
injections for diabetes) and parents will be taught how to administer the shots to their
child. Blood samples, usually be between 30 to 90 milliliters (2 to 6 tablespoons), will be
drawn just before starting medication and again 1 day, 1 week, 1 month, 3 months and 4
months after therapy begins. At these same time intervals, patients will provide a
salt-water mouth rinse specimen, which will be tested for changes in the number of white
blood cells during interferon gamma treatment.
Patients will be admitted to the NIH Clinical Center for inpatient evaluations at the start
of therapy and again after 1 week, 1month, 3 months and 4 months. The initial screening
visit will take a few days and subsequent visits will take 1 to 2 days.
Leukocyte adhesion deficiency type I (LAD I) is a primary immunodeficiency disease resulting
from mutations in the gene encoding CD18. Markedly reduced or absent expression of the
leukocyte integrin component CD18 causes significant impairment in leukocyte mobilization to
inflammatory sites. Clinically, patients have marked leukocytosis and recurrent infections
involving soft tissues such as skin, the gastrointestinal tract and gingiva. Death due to
infections in early infancy is common with the severe form of LAD I (CD18 expression less
than 0.5%), but patients with the moderate phenotype (CD18 expression 1-10%) may survive
into young adulthood. To date, therapy consists of antibiotic treatment for infections and
bone marrow transplantation when possible. LAD I is also a candidate for future gene
therapy. Recently, it has been shown that in vivo administration of interferon gamma
(IFN-gamma) upregulates CD18 expression in normals and alters leukocyte trafficking. We
hypothesize that modest increases in CD18 expression in LAD I patients with the moderate
phenotype or alterations in CD18 independent trafficking could result in detectable clinical
changes and possible clinical improvement.
PARTICIPANT INCLUSION CRITERIA:
Leukocyte Adhesion Deficiency type I, as determined by flow cytometry showing less than
10% CD18 expression in association with typical signs of LAD I .
Weight adequate to permit the blood drawing requirements of the protocol, greater than 13
Patients should be without serious, ongoing, uncontrolled infections.
Adequate hematopoietic, renal and hepatic function, defined as:
Absolute neutrophil count greater than or equal to 1500/microL;
Hemoglobin greater than or equal to 7g/dL (post transfusion or erythropoeitin);
Platelet count greater than or equal to 100,000/microL;
Creatinine less than or equal to 1.5 x upper limit of normal;
Bilirubin less than or equal to 1.5 x upper limit of normal;
AST/SGOT less than or equal to 2.5 x upper limit of normal;
ALT/SGPT less than or equal to 2.5 x upper limit of normal;
Calculated Creatinine Clearance greater than or equal to 60 mL/min.
Karnofsky Performance Status Index greater than or equal to 70.
Written signed informed consent.
PARTICIPANT EXCLUSION CRITERIA:
Symptomatic cardiac disease or ongoing treatment for same.
Pregnant or lactating women.
Surgery during the two weeks prior to the start of IFN-gamma dosing.
Concurrent use of systemic corticosteroids, except for physiologic replacement.
Exposure to any investigational drug within four weeks prior to the start of dosing.
Any other major illness which, in the investigator's judgement, may substantially increase
the risk associated with the patients participation in this study.