Recent evidence suggests that an interaction of noradrenaline (NE) and cortisol (CORT) during encoding leads to greater consolidation of emotional memories. Convergent models of posttraumatic stress disorder (PTSD) suggest the release of CORT and NE lead to greater intrusive memories in PTSD. This study examined the effect of NE and CORT during encoding on recall and intrusive memories in PTSD. Fifty-eight participants (18 participants with PTSD, 20 trauma-exposed controls, and 20 non-trauma exposed controls) provided saliva samples of NE (indexed by salivary alpha amylase; sAA) and CORT at (a) baseline and (b) after viewing negative emotional stimuli. Delayed memory recall and number of intrusive memories of negative, neutral and positive stimuli were recorded two days after this initial testing session. The PTSD group had greater NE levels to negative stimuli and reported greater numbers of intrusive memories of negative stimuli than controls. Regression analyses revealed that the interaction of CORT and NE significantly predicted negative intrusive memories in the PTSD group. The trauma-exposed group reported significantly greater recall of negative images compared to controls, but did not differ significantly from the PTSD group. The PTSD group reported greater levels of suppression of negative images during encoding compared to the other groups. Our results confirm that the interaction of NE and CORT significantly predicts greater negative intrusive memories, but this occurs specifically in the PTSD group. This suggests that a level of heightened arousal is required for the relationship between stress hormones and emotional memory to manifest in PTSD.
Gene-engineering of T cells offers the possibility of uniformly changing the characteristics of their immune responses. The ability to direct polyclonal T cells to a single antigenic specificity is a powerful tool with which to probe anti-tumour immune responses, and in turn ask which tumour antigens represent the best targets for immune therapy. The intracellular components of TCR signalling pathways can also be manipulated to optimise anti-tumour responses. Such manipulated T cells may in the future represent an important adjunctive therapy alongside allogeneic haematopoietic stem cell transplantation (ASCT), in order to specifically boost a graft versus leukaemia (GVL) effect. In addition, the ability to confer a suppressive phenotype to CD4 cells or to engineer a susceptibility gene into effector cells provides new therapeutic avenues for graft versus host disease (GVHD), the most challenging adverse effect arising post ASCT. Within this review, mechanisms of GVL and GVHD are discussed and we consider how they may be separated through T cell gene engineering. In addition, we highlight recently investigated safety issues which will impact the future clinical application of gene-manipulated immune cells.
Chronic myeloid leukemia (CML) is a clonal stem cell disorder that is characterized by the acquired chromosomal translocation BCR-ABL. This gives rise to a constitutively active tyrosine kinase deregulation of the normal mechanisms of cell cycle control. In the normal hematopoietic system, hematopoietic stem cells (HSC) self-renew to form identical daughter cells but also differentiate to mature blood cells. Leukemic stem cells (LSC) share these properties of self-renewal and also differentiate to mature leukemic cells. LSC have been isolated from patients with CML: these cells give rise to leukemia following transplantation into NOD-SCID mice models. Further characterization of CML stem cells has demonstrated that a small percentage of these cells are quiescent despite culture with growth factors. The CML stem cell arises from a normal HSC that has acquired the Philadelphia chromosome. In advanced phase, more mature cells such as granulocyte/monocyte progenitors might also acquire the ability to self-renew and function as LSC. This might be one of the mechanisms underlying the progression to blast crisis. Quiescent stem cells are resistant to treatment with imatinib in vitro and are thought also to show resistance in vivo. The properties of the stem cells that lead to this drug resistance are still being characterized. However, this drug insensitivity leads to disease persistence that may lead to disease relapse even despite an initial response to imatinib. Newer molecular therapies are in development that act to specifically target and eradicate the stem cell pool.
Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors.
Adoptive immunotherapy using TCR gene modified T cells may allow separation of beneficial Graft versus tumour responses from harmful GvHD. Improvements to this include methods to generate high avidity or high affinity TCR, improvements in vector design and reduction in mispairing. Following adoptive transfer, TCR transduced T cells must be able to survive and persist in vivo to give most effective antitumour responses. Central memory or naive T cells have both been shown to be more effective than effector cells at expanding and persisting in vivo. Lymphodepletion may enhance persistence of transferred T cell populations. TCR gene transfer can be used to redirect CD4 helper T cells, and these could be used in combination with CD8+ tumour specific T cells to provide help for the antitumour response. Antigen specific T regulatory T cells can also be generated by TCR gene transfer and could be used to suppress unwanted alloresponses.
There is increasing evidence that disgust responding occurs at both a primary and secondary level in the form of disgust propensity and disgust sensitivity. The unique contributions of anxiety and disgust need to be established if disgust is to be implicated in the etiology of anxiety disorders such as obsessive-compulsive disorder (OCD). The primary objective of the current study was to develop two separate implicit measures of disgust propensity and sensitivity and to explicate the role of implicit disgust propensity and sensitivity in avoidance behavior and OC tendencies.
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