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Allogenic hematopoietic stem cell transplantation is a therapeutic procedure performed over a wide range of donor and recipient age combinations, representing natural experiments of how the age of the recipient affects aging in transplanted donor cells in vivo. We measured DNA methylation and epigenetic aging in donors and recipients and found that biological epigenetic clocks are accelerated in cells transplanted into an older body and decelerated in a younger body. This is the first evidence that the age of the circulating environment influences human epigenetic aging in vivo. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus- (EBV-) induced posttransplantation lymphoproliferative disease (PTLD) is a life-threatening complication following allogeneic stem cell transplantation. The main risk factor is anti-thymocyte globulin (ATG). Patients who fail first-line treatment with rituximab have a poor prognosis. Though adoptive transfer of EBV-specific T cells is a potentially effective option, it is not readily available. In this case report, the patient developed PTLD following transplantation for aplastic anemia using ATG as part of the conditioning. He failed rituximab treatment and developed graft failure. We were aware that the stem cell donor had a recent EBV infection prior to transplantation, whereas the patient most likely was EBV negative before transplant. We describe our strategy to meet the patient's urgent need for EBV-specific T cells, as well as new hematopoietic stem cells. The same donor was used for a second transplant, using peripheral blood stem cells. The conditioning used was thiotepa/busulfan/fludarabin with a single dose of cyclophosphamide after transplant as graft-versus-host disease (GVHD) prophylaxis. The EBV DNA levels fell when conditioning was started, and have been undetectable since day +15 and remained so till 18 months after transplantation. The patient is doing well. This case reports successful use of cyclophosphamide after transplantation as GVHD prophylaxis, preserving virus-specific immunity. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD. [ABSTRACT FROM AUTHOR]

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is influenced by many factors (underlying disease, HLA-matching, patient and donor age, CMV serostatus, co-morbidities, conditioning regimen, GVHD prophylaxis and graft source and composition). The number of T-cells contained in the graft is associated with the incidence and severity of GvHD. The effect of CD34+ cell dose in HSCT on overall survival and incidence of acute and chronic GvHD is less well established. We analyzed transplant outcomes in 189 patients with hematological malignancy and sibling donor receiving G-CSF mobilized peripheral blood stem cell grafts. Myeloablative conditioning was given to 88 patients and reduced intensity conditioning to 101 patients. Median CD34+ cell dose was 5.6 × 106/kg (0.6-17.0). Anti-thymocyte globulin (ATG) was not given. Median time to neutrophil engraftment (ANC >0.5 × 109/L) was 17 days. In multivariate analysis <5 × 106/CD34+ cells/kg correlated to slower engraftment, measured as later than median days-to-engraftment (OR 2.62, 95% CI 1.27-5.41, p=0.008). The 5-year overall survival (OS) for all patients was 47%. The best 5-year OS (71%) was seen in patients receiving 6-7 × 106CD34+cells/kg (HR: 0.43, 95% CI: 0.24-0.78, p=0.005) (fig 1). Transplant related mortality at 1 and 5 years was 19% and 28%, respectively. The lowest TRM (15%) was found among patients given a CD34+ cell dose of 6-7 × 106cells/kg (HR: 0.41, 95% CI: 0.18-0.92, p=0.03). The cumulative incidence of relapse (RI) for all patients was 29%. Increased RI (41%) was found in patients who received <5 × 106cells/kg CD34+ cells (HR: 1.89, 95% CI: 1.09-3.29, p=0.024). In total, 86 (46%) and 92 (56%) patients developed acute and chronic GvHD, respectively. The cumulative incidence of acute GVHD grades II-IV in the whole cohort was 40%. The lowest incidence (33%) of aGVHD II-IV was found among patients receiving a high cell-dose. In the corrected multivariate analysis, a CD34+ cell dose of >6.5 × 106cells/kg was associated with a lower incidence of aGVHD II-IV (RH: 0. 53, 95% CI: 0.29-0.97, p=0.04). In the corrected multivariate analysis a CD34 cell dose of 6-7 × 106/kg was associated with better OS and lower TRM, while a CD34 cell-dose of <5 × 106/kg was associated with more relapse and less cGVHD. A high CD34 cell-dose (>7 × 106/kg) correlated to less aGVHD II-IV. The CD34 cell dose has impact on the outcome in sibling donor HSCT using peripheral-blood stem-cells. [ABSTRACT FROM AUTHOR]