Abstract
Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.
Highlights
The inborn error of immunity (IEI) caused by bi-allelic dedicator of cytokinesis 8 (DOCK8) deficiency was first described in 2009 by Zhang et al [1]
Given the fact that DOCK8 deficiency affects many hematopoietic lineages, we reasoned that reversal of disease phenotype after hematopoietic stem cell transplantation (HSCT) would depend on the level of cell lineage-specific donor chimerism
P2 was the first patient ever reported with successful HSCT for DOCK8 deficiency; transplantation in 2004 preceded the first description of the underlying genetic cause [20]
Summary
The inborn error of immunity (IEI) caused by bi-allelic dedicator of cytokinesis 8 (DOCK8) deficiency was first described in 2009 by Zhang et al [1]. Treosulfan or reduced-dose busulfan-based reduced toxicity regimens offer less short-term and possibly long-term toxicity [24] They do not always result in complete donor chimerism of all cell lineages, which—depending on the underlying condition—may or may not result in reversal of the disease phenotype [25]. Given the fact that DOCK8 deficiency affects many hematopoietic lineages, we reasoned that reversal of disease phenotype after HSCT would depend on the level of cell lineage-specific donor chimerism. We here report detailed analysis of long-term clinical outcome, lineage-specific chimerism, laboratory parameters, and pulmonary function tests of nine patients who underwent HSCT for DOCK8 deficiency between 2004 and 2017, four of whom with ensuing variable degrees of mixed chimerism
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