The nuclear factor erythroid 2-related factor 2 agonist tert-butylhydroquinone improves bone marrow mesenchymal stromal cell function in prolonged isolated thrombocytopenia after allogeneic haematopoietic stem cell transplantation.

Prolonged isolated thrombocytopenia (PT) is a life-threatening comorbidity associated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Our previous study indicated that dysfunctional bone marrow mesenchymal stromal cells (BM MSCs) played a role in PT pathogenesis and that reactive oxygen species (ROS) accumulation was related to BM MSC senescence and apoptosis. However, the mechanism of the increase in ROS levels in the BM MSCs of PT patients is unknown. In the current case-control study, we investigated whether nuclear factor erythroid 2-related factor 2 (NRF2), which is a central regulator of the cellular anti-oxidant response that can clear ROS in human BM MSCs, was associated with PT after allo-HSCT. We evaluated whether an NRF2 agonist (tert-butylhydroquinone, TBHQ) could enhance BM MSCs from PT patients in vitro. We found that BM MSCs from PT patients exhibited increased ROS levels and reduced NRF2 expression. Multivariate analysis showed that low NRF2 expression was an independent risk factor for primary PT [p = 0.032, Odds ratio (OR) 0.868, 95% confidence interval (CI) 0.764-0.988]. In-vitro treatment with TBHQ improved the quantity and function of BM MSCs from PT patients by downregulating ROS levels and rescued the impaired BM MSC support of megakaryocytopoiesis. In conclusion, these results suggested that NRF2 downregulation in human BM MSCs might be involved in the pathogenesis of PT after allo-HSCT and that BM MSC impairment could be improved by NRF2 agonist in vitro. Although further validation is needed, our data indicate that NRF2 agonists might be a potential therapeutic approach for PT patients after allo-HSCT.

A retrospective analysis on anti-CD20 antibody-treated Epstein-Barr virus-related posttransplantation lymphoproliferative disorder following ATG-based haploidentical T-replete hematopoietic stem cell transplantation.

Posttransplantation lymphoproliferation disorder (PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). Anti-CD20 antibody is the most widely used antibody to eliminate infected B cells. Few studies have focused on prognostic factors predicting the outcome of EBV (Epstein-Barr virus)-PTLD. We conducted a retrospective analysis of 2571 haplo-HSCTs performed between 2010 and 2017 at the Peking University Institute of Hematology; seventy patients who had been treated with rituximab for PTLD were enrolled. The overall EBV-related PTLD frequency was 3.1%. With a median follow-up time of 365 days (range, 54-2659), the overall survival rate was 51.43% (36/70). The cumulative incidence of EBV-PTLD complete remission with anti-CD20 antibody monotherapy was 68.57% (48/70). EBV-PTLD-related mortality was 11.43% (8/70), while the transplantation-related mortality was 38.57% (27/70). Multivariate analysis showed that a decrease in EBV viral load 1 week after therapy was associated with high response rate of EBV-PTLD (p = 0.007, 0.106 (0.021-0.549)), low PTLD-related mortality (p = 0.010, HR 0.058 (0.007-0.503)), and transplantation-related mortality (p = 0.051, HR 0.441 (0.194-1.003)). For EBV-PTLD patients after haplo-HSCT who received rituximab as first-line therapy, non-decreased EBV viral load 1 week after anti-CD20 therapy could be high risk factor for poor outcomes.

Delay expression of NKp30 on NK cells correlates with long-term mycophenolate mofetil treatment and higher EBV viremia post allogenic hematological stem cells transplantation.

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p = .04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.

Recipient-donor KIR ligand matching prevents CMV reactivation post-haploidentical T cell-replete transplantation.

Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation. Donor-recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post-transplantation. In addition, the percentage of γ-interferon expression on donor-derived NK cells was significantly higher in the recipients among the recipient-donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft-versus-host or host-versus-graft direction mismatch on days 30 and 100 post-transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor-recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation.