Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT.

Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4+ and CD8+ components of the CMV-specific immune response in protection from reactivation is unclear. The CMV-specific CD4+ and CD8+ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4+ and CD8+ responses, respectively. A deficient CMV-specific CD4+ T-cell immune response within the first 30-50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4+ and CD8+ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4+ T cells correlated with CMV-specific CD8+ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4+ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4+ immune response is useful in managing viral reactivation following HSCT

Making subaltern shikaris: histories of the hunted in colonial central India

Academic histories of hunting or shikar in India have almost entirely focused on the sports hunting of British colonists and Indian royalty. This article attempts to balance this elite bias by focusing on the meaning of shikar in the construction of the Gond ‘tribal’ identity in late nineteenth and early twentieth-century colonial central India. Coining the term ‘subaltern shikaris’ to refer to the class of poor, rural hunters, typically ignored in this historiography, the article explores how the British managed to use hunting as a means of state penetration into central India’s forest interior, where they came to regard their Gond forest-dwelling subjects as essentially and eternally primitive hunting tribes. Subaltern shikaris were employed by elite sportsmen and were also paid to hunt in the colonial regime’s vermin eradication programme, which targeted tigers, wolves, bears and other species identified by the state as ‘dangerous beasts’. When offered economic incentives, forest dwellers usually willingly participated in new modes of hunting, even as impact on wildlife rapidly accelerated and became unsustainable. Yet as non-indigenous approaches to nature became normative, there was sometimes also resistance from Gond communities. As overkill accelerated, this led to exclusion of local peoples from natural resources, to their increasing incorporation into dominant political and economic systems, and to the eventual collapse of hunting as a livelihood. All of this raises the question: To what extent were subaltern subjects, like wildlife, ‘the hunted’ in colonial India

Unique features and clinical importance of acute alloreactive immune responses

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation

Prediction of Allogeneic Hematopoietic Stem-Cell Transplantation Mortality 100 Days After Transplantation Using a Machine Learning Algorithm: A European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. PATIENTS AND METHODS: This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. RESULTS: OM prevalence at day 100 was 13.9% (n=3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100-day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; P<.001). Calibration was excellent. Scores assigned were also predictive of secondary objectives. CONCLUSION: The alternating decision tree model provides a robust tool for risk evaluation of patients with AL before HSCT, and is available online (http://bioinfo.lnx.biu.ac.il/∼bondi/web1.html). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT

Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia

This study aimed to determine the impact of tyrosine kinase inhibitors given pre- and post- allogeneic stem cell transplantation on long- term outcome of patients allografted for Philadelphia chromosome- positive acute lymphoblastic leukemia. This retrospective analysis from the EBMT Acute Leukemia Working Party included 473 de novo Philadelphia chromosome- positive acute lymphoblastic leukemia patients in first complete remission who underwent an allogeneic stem cell transplantation using a human leukocyte antigen- identical sibling or human leukocyte antigen- matched unrelated donor between 2000 and 2010. Three hundred and ninety patients received tyrosine kinase inhibitors before transplant, 329 at induction and 274 at consolidation. Kaplan- Meier estimates of leukemia- free survival, overall survival, cumulative incidences of relapse incidence, and non- relapse mortality at five years were 38%, 46%, 36% and 26%, respectively. In multivariate analysis, tyrosine- kinase inhibitors given before allogeneic stem cell transplantation was associated with a better overall survival ( HR= 0.68; P= 0.04) and was associated with lower relapse incidence ( HR= 0.5; P= 0.01). In the post- transplant period, multivariate analysis identified prophylactic tyrosine- kinase inhibitor administration to be a significant factor for improved leukemiafree survival ( HR= 0.44; P= 0.002) and overall survival ( HR= 0.42; P= 0.004), and a lower relapse incidence ( HR= 0.40; P= 0.01). Over the past decade, administration of tyrosine kinase inhibitors before allogeneic stem cell transplantation has significantly improved the long- term allogeneic stem cell transplantation outcome of adult Philadelphia chromosome- positive acute lymphoblastic leukemia. Prospective studies will be of great interest to further confirm the potential benefit of the prophylactic use of tyrosine kinase inhibitors in the post- transplant setting.Peer reviewe

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C