NIH Research Festival
Dogs with canine leukocyte adhesion deficiency or CLAD, similar to children with LAD-1, suffer from recurrent bacterial infections and early death due to the absence of the CD18 integrin on leukocytes. In CLAD dogs treated by gene therapy, peripheral blood analysis of T-cell subsets demonstrated an expansion of CD18+ T-cell populations over time. All four dogs were treated as 6-8-week-old CLAD pups with a reduced intensity conditioning regimen prior to infusion of CD34+ cells transduced with a foamy viral vector containing CD18. Peripheral blood obtained over 8 years was analyzed for myeloid and lymphoid subsets, and for gene correction by CD18 expression. Overall CD18+ leukocyte levels in the peripheral blood ranged from 2-13% at 8 years. CD18+ T-cell levels in the peripheral blood were notable, with CD18+ T-cell levels at 14-19% at 1 year post infusion, expanding to 36-54% by 8 years. Effector and memory T-cells showed a population bias of CD18+ CD4+ cells (39% vs 17% CD18–, 14% vs 8% CD18–, respectively). Naïve cells were disproportionately represented in CD18– CD4+ subsets (68% vs 32% CD18+). In conclusion, treated CLAD dogs provide a unique model to assess the role of CD18 in long-term T-cell subset maintenance and interactions. Memory T-cells in all cases were expanded in CD18+ T-cell compartments, whereas naïve T-cells were more highly prevalent in CD18– T-cell compartments. Therefore, newly arising CD18+ T-cells receive a strong selective advantage in antigen stimulation, leading to the increased presence of CD18+ cells in T-cell memory compartments over time.
Scientific Focus Area: Immunology
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