Impact of CD34+ cell dose in children who receive unrelated PBSCT with in vivo T-cell depletion for hematologic malignancies.

PBSCs are increasingly being chosen as the mode of donation among unrelated donors. Pediatric patients, in particular, may receive very high CD34(+) and CD3(+) doses during unrelated PBSCT. In this work, we analyzed survival and GVHD outcomes in a cohort of 81 children who received unrelated PBSCT with uniform antithymocyte globulin (ATG)-based in vivo T-cell depletion for treatment of hematologic malignancy, with emphasis on the impact of cell dose on transplant outcomes. EFS was 61.5±5.6%, with higher CD34(+) dose (>10.0 × 10(6)/kg) and lower patient risk status predicting improved survival in multivariate study. Cumulative incidence of relapse was 30.2±5.2%; a low CD34(+) dose was the only significant factor for relapse. Neither CD34(+) nor CD3(+) dose was a significant determinant of acute or chronic GVHD. Importance of CD34(+) dose was reaffirmed in a subcohort of younger patients who received greater median cell doses than the overall cohort. In summary, for children who received unrelated PBSCT with ATG-based T-cell depletion for treatment of hematologic malignancy, the CD34(+) dose was the most important factor for relapse and EFS, and neither the CD34(+) nor the CD3(+) dose influenced incidence of acute or chronic GVHD.

High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept­resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies.

Two children with differing outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation.

Tuberculosis (TB) is a rare infectious complication after hematopoietic stem cell transplantation (HSCT), but may be more significant in areas where the disease is endemic. Here, we present the clinical course of 2 children with acute lymphoblastic leukemia who were diagnosed with pulmonary TB after allogeneic HSCT. Both patients were treated for either probable or possible invasive fungal infection, as well as TB. One patient, diagnosed with TB 3 months after HSCT, showed remittent fever and symptoms that progressed to acute respiratory distress syndrome and death, despite 3 modifications to the anti-TB regimen. In contrast, another patient who was diagnosed with TB 8 months after transplantation, responded well to anti-TB medication and completed 1 year of treatment with resolution of lung lesions. Co-morbid opportunistic infections, profound host immunosuppression early after transplantation, and potential risk of multi-drug resistant-TB may act as major barriers to effective treatment of TB after HSCT despite appropriate anti-TB medication.

Effects of synthesized voice warning parameters on perceived urgency.

The effects of synthesized voice warning parameters on perceived urgency were examined in order to build a detailed and usable description of the relation between the parameters of synthesized voice warnings and perceived urgency. Ten native and 10 non-native English speakers participated in 4 experiments to evaluate and quantify the effects of the voice parameters. The results showed that speech rate, average fundamental frequency [F(0)], voice type, and fundamental frequency contour have clear effects on the perceived urgency of synthesized voice warnings. The effects of quantitative parameters on perceived urgency were scaled using an application of Stevens's power law (1957). In addition, the results showed significant differences in the perceived urgency of average F(0) and F(0) contour types between native and non-native English speakers. Implications of the results for the design and improvement of synthesized voice warnings are discussed.