Thiol/redox metabolomic profiling implicates GSH dysregulation in early experimental graft versus host disease (GVHD).

Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation (BMT). Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol/redox metabolomics was used to identify metabolic perturbations associated with early preclinical (Day+4) and clinical (Day+10) stages of GVHD by comparing effects in Syngeneic (Syn; major histocompatibility complex- identical) and allogeneic transplant recipients (Allo BMT) in experimental models. While most metabolic changes were similar in both groups, plasma glutathione (GSH) was significantly decreased, and GSH disulfide (GSSG) was increased after allogeneic compared to syngeneic recipient and non-transplant controls. The early oxidation of the plasma GSH/GSSG redox couple was also observed irrespective of radiation conditioning treatment and was accompanied by significant rise in hepatic protein oxidative damage and ROS generation. Despite a significant rise in oxidative stress, compensatory increase in hepatic GSH synthesis was absent following Allo BMT. Early shifts in hepatic oxidative stress and plasma GSH loss preceded a statistically significant rise in TNF-α. To identify metabolomic biomarkers of hepatic GVHD injury, plasma metabolite concentrations analyzed at Day+10 were correlated with hepatic organ injury. GSSG (oxidized GSH) and ß-alanine, were positively correlated, and plasma GSH cysteinylglycine, and branched chain amino acids were inversely correlated with hepatic injury. Although changes in plasma concentrations of cysteine, cystathionine (GSH precursors) and cysteinylglycine (a GSH catabolite) were not significant by univariate analysis, principal component analysis (PCA) indicated that accumulation of these metabolites after Allo BMT contributed significantly to early GVHD in contrast to Syn BMT. In conclusion, thiol/redox metabolomic profiling implicates that early dysregulation of host hepatic GSH metabolism and oxidative stress in sub-clinical GVHD before elevated TNF-α levels is associated with GVHD pathogenesis. Future studies will probe the mechanisms for these changes and examine the potential of antioxidant intervention strategies to modulate GVHD.

Improved engraftment with minimal graft-versus-host disease after major histocompatibility complex-mismatched cord blood transplantation with photochemically treated donor lymphocytes.

There is a significant risk of severe graft-versus-host disease (GVHD) and graft failure after unrelated umbilical cord blood transplantation (CBT) if donor-recipient pairs are mismatched at major histocompatibility complex (MHC) loci. To mitigate these risks after MHC-mismatched CBT, we infused psoralen-treated, photochemically inactivated, mature donor T-lymphocytes with MHC (H2-haplotype) mismatched murine donor fetal near-term peripheral blood (FNPB) cells after sublethal irradiation. We analyzed the rates of donor engraftment, GVHD and long-term survival in H2 haplotype disparate (C57BL/6 [H-2(b)/Thy1.1] → AKR [H-2(k)/Thy1.2]) recipient mice. We observed inconsistent donor engraftment after transplantation with cord blood alone, but superior engraftment and long-term survival after FNPB transplantation supplemented with psoralen-treated donor T-lymphocytes. Additionally, there was fatal GVHD after FNPB co-infusion with untreated donor T-lymphocytes, but minimal GVHD after FNPB supplemented with psoralen-treated donor T-lymphocytes transplantation. Donor MHC(high)/c-Kit(+)/lineage(-)/CD34(-) stem cells were noted in the recipient bone marrow compartment following co-infusion of photochemically inactivated T-cells with FNPB. Despite the non-myeloablative preparation before FNPB infusion, complete hematological recovery was delayed until 50-60 d after transplantation. We observed that co-transplantation of psoralen-treated donor T-lymphocytes with FNPB facilitated durable engraftment of donor hematopoietic stem cells in the marrow and splenic compartments with complete but delayed recovery of all hematopoietic lineages. This CBT model establishes the possibility of ensuring donor engraftment across a MHC barrier without severe GVHD.

Umbilical cord blood transplantation for thalassemia major.

Hematopoietic cell transplantation is curative therapy for thalassemia major. Although the clinical application of hematopoietic cell transplantation has relied on marrow collected from related and unrelated donors as the primary source of donor hematopoietic cells, umbilical cord blood (UCB) is an alternative source of hematopoietic cells and represents a suitable allogeneic donor pool in the event that a marrow donor is not available. Progress in developing UCB transplantation for thalassemia is reviewed and the most likely areas of future clinical investigation are discussed.

The utility of routine surveillance blood cultures in asymptomatic hematopoietic stem cell transplant patients.

INTRODUCTION: Surveillance blood cultures (BCs) are often obtained in hematopoietic stem cell transplant (HSCT) patients for earlier detection of blood stream infections (BSI). The major aim of this study was to determine the utility of the current practice of obtaining surveillance blood cultures from asymptomatic transplant patients upon admission for the preparative regimen. METHODS: We conducted an 8-year retrospective study of all patients consecutively admitted to the hospital for a HSCT from 2000 to 2008. RESULTS: In this retrospective analysis, surveillance BCs from 191 eligible patients were analyzed. The incidence of definitive BSIs was 0.52% (1/191) with 6 BCs from other HSCT patients growing probable contaminants. The overall incidence of positive surveillance BCs was 2.9% (7/238) for the BCs taken and 3.7% (7/191) for patients cultured with coagulase negative staphylococcus being isolated from 6 of the 7 patients. The probability of increased BSI after transplantation in patients with initial positive surveillance BCs compared with those having negative BCs, was not significant (P=0.675). No infection-related mortality was observed during the first 60 days posttransplantation in these patients. CONCLUSIONS: The frequency of positive surveillance BCs in asymptomatic HSCT patients at the time of hospital admission for transplant seems to be extremely low. These results, if confirmed by larger studies, show the reduced utility of obtaining surveillance BC in asymptomatic patients before administration of the conditioning regimen and the need for re-evaluation of this practice.