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Matched unrelated bone marrow transplantation with reduced-intensity conditioning for leukocyte adhesion deficiency

Bone Marrow Transplantation volume 37, pages 717–718 (2006)Cite this article

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder characterized by impaired migration of cells of the innate immune system, primarily neutrophils, from the intravascular space.1 This migratory defect stems from impaired adhesion of marginated neutrophils to the vascular endothelium, thereby pre-empting neutrophil diapedesis and localized antimicrobial activity. Normally, stable neutrophil adhesion is mediated by interactions between β2 leukocyte integrins (CD11/CD18) and counter ligands of the intercellular adhesion molecule family inducibly expressed on endothelial cell surfaces at inflammatory foci.2 Leukocyte adhesion deficiency syndromes stem from dysfunction of neutrophil migration. Three forms of LAD have been described.3 LAD1, the predominant form, stems from absent or severely impaired CD18 expression, preventing the stable leukocyte–endothelial engagement necessary for neutrophil egress from microvasculature. Severe LAD, regardless of the molecular defect, results in frequent and potentially fatal infections. The treatment of LAD has been problematic. Although intense antibiotic therapy and granulocyte transfusion are used during acute infectious episodes, children with LAD frequently die from infectious sequelae during the first 5 years of life.4 Although retrovirus-mediated gene therapy has been attempted, the only curative treatment for LAD is allogeneic stem cell transplant (SCT). Pre-clinical data suggest that donor chimerism of only 5% may be sufficient to protect patients with LAD from recurrent pyogenic infections post transplant.5, 6, 7, 8 As such, strategies that maximize the probability of engraftment and donor tolerance while minimizing toxicity may be particularly efficacious in definitive LAD treatment.

The patient is a 20-year-old male, diagnosed shortly after birth with LAD, following delayed umbilical cord scission and concurrent omphalitis with Pseudomonas sepsis. Early disease manifestations included recurrent sinopulmonary infections and persistent skin ulcerations of the extremities, groin, scrotum and perirectal areas. Aggressive supportive care measures included surgical debridement, maggot instillation and split thickness skin grafting. The patient was regularly hospitalized for serious bacterial infections, and on several occasions required donor leukocyte infusions. An attempt at definitive therapy was made using retrovirus-mediated CD18 gene replacement, which ultimately was unsuccessful. The patient was referred for SCT as a means of potential cure for LAD1. Pre-transplant evaluation was significant for dental disease and a 4 cm ulcerated lesion in the groin. A reduced-intensity transplant was planned and approved by the Institutional Review Board at Vanderbilt University.

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Authors and Affiliations

  1. Pediatric Stem Cell Transplant Program, Vanderbilt University, Nashville, TN, USA

    M E Engel, C Calder, B Manes & H Frangoul

  2. Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD, USA

    D D Hickstein & T R Bauer Jr

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  1. M E Engel
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  2. D D Hickstein
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  3. T R Bauer Jr
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  4. C Calder
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  5. B Manes
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  6. H Frangoul
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Engel, M., Hickstein, D., Bauer, T. et al. Matched unrelated bone marrow transplantation with reduced-intensity conditioning for leukocyte adhesion deficiency. Bone Marrow Transplant 37, 717–718 (2006). https://doi.org/10.1038/sj.bmt.1705301

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