Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocyte adhesion deficiency (LAD) is an autosomal recessive immunodeficiency disease characterized by severe, recurrent bacterial infections. In patients with LAD, the leukocytes, particularly the neutrophils, fail to adhere to the endothelial cell wall and migrate to the site of infection. LAD results from heterogeneous molecular defects in the leukocyte integrin CD18, which prevent CD11/CD18 heterodimer formation and surface expression. To date, hematopoietic stem cell transplantation remains the only curative treatment for LAD, however, this approach is limited by transplant-related toxicities and graft-versus-host disease. During the course of the preceding decade we have conducted extensive experimental studies demonstrating that gene transfer of the CD18 subunit corrects the structural and functional defect in LAD leukocytes. These studies provided the support for the initiation of a clinical trial of retroviral-mediated gene transfer of CD18 in two patients with the severe deficiency phenotype or LAD. This review will present an overview of LAD, preclinical CD18 gene transfer studies and the initial results from the current clinical trial.
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PMID:Gene therapy for leukocyte adhesion deficiency. 1124 68

Leukocyte adhesion deficiency type I (LAD-I) is an inherited immunodeficiency disorder caused by defective expression of the leukocyte integrins, namely, lymphocyte function-associated antigen 1, Mac-1, and p150, 95, and is associated with obstructed cell adhesion, migration, and phagocytosis. Patients suffer from various bacterial or fungal infections and their prognoses are poor. The only curative treatment is hematopoietic stem cell transplantation. Conventional myeloablative transplantations have been performed, but with unsatisfactory results. We performed the first successful nonmyeloablative unrelated marrow transplantation for a 20-year-old female LAD-I patient, who suffered from recurrent and occasionally life-threatening infections such as cellulitis, gingivostomatitis, and sepsis. We adopted a preparative regimen with fludarabine, cyclophosphamide, and low-dose total-body irradiation, and tacrolimus and short-term methotrexate as immunosuppressants. This procedure was sufficiently immunosuppressive to obtain stable engraftment without remarkable complications, and graft-versus-host disease was controllable. Dramatic improvement of her disease was observed, supported by the normal expressions of integrins. Twenty one months after transplantation, she is well with a Karnofsky score of 100. Thus, nonmyeloablative transplantation is considered a feasible method for LAD-I.
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PMID:Successful nonmyeloablative bone marrow transplantation for leukocyte adhesion deficiency type I from an unrelated donor. 1767 74