T‐cell alloreactivity dominates natural killer cell alloreactivity in minimally T‐cell‐depleted HLA‐non‐identical paediatric bone marrow transplantation

Abstract

Summary. Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin‐like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T‐cell‐depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T‐cell alloreactivity. We investigated the relative significance of NK‐cell and T‐cell alloreactivity in 105 paediatric patients who received a minimally T‐cell‐depleted human leucocyte antigen‐non‐identical BM transplantation. Donor NK‐cell incompatibility did not improve patient outcome [engraftment, graft‐versus‐host disease (GVHD), relapse or overall survival]. In contrast, donor T‐cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T‐cell alloreactivity dominated that of NK cells in minimally T‐cell‐depleted grafts.

Fully functional NK cells after unrelated cord blood transplantation

“…As currently described, CB contains only little Functional NK cells after UCBT V Beziat et al or no cytotoxic T cells directed against viral and bacterial peptides, which may cross-react with HLA alloantigens, and thus may be responsible for the lower-than-expected frequency of severe GvH disease, even in the setting of one or two HLA mismatched. 46,47 Similarly, in this study, less than 32% of patients presented an acute grade II or III GvH disease, and no patient presented an acute grade IV graft-versus-host disease, which could be due to the lack of post-thymic T cells and the naivety of the T-cell function after UCBT observed earlier after haploidentical HSCT. 48,49 However, we have shown earlier that following haploidentical HSCT, relapse occurred in the early post-transplantation period in 7-10 patients (70%), despite the KIR-ligand incompatibility between donor and recipient.…”

Does haploidentical transplantation in children with primary immunodeficiencies have the potential to exploit donor NK cell alloreactivity?

“…Therefore, T-cell alloreactivity due to the HLA mismatch might have obscured NK cell alloreactivity, as recently observed in pediatric patients with hematological malignancies. 6 However, the percentage of patients who received o3 Â 10 4 /kg T cells was almost the same in the two patient groups (67% in patients with and 72% in those without KIR-ligand mismatch). ATG-based GVHD prophylaxis has been proposed as a means of facilitating recovery of donor NK cells.…”

“…Indeed, several retrospective attempts to assess the benefits of NK cell alloreactivity in KIR ligand-mismatched unrelated-donor HCT for hematological malignancies have provided discrepant results. [4][5][6] Differences in diagnoses, CRs, graft composition, and GVHD prophylaxis may account for these controversial results in patients who were all transplanted for malignant hematological diseases. In our patients, no post-transplant immune suppression was given as GVHD prophylaxis.…”

New strategies for haploidentical transplantation

“…In T-cell-replete or poorly T-cell-depleted allogeneic transplantation, the effect of alloreactive NK cells might be overridden by alloreactive T cells requiring intensive pharmacologic GvHD prophylaxis (62). This could explain the deleterious effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion that were seen (63).…”