A study of regulatory T cells in allogeneic haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is an established therapy for many haematological disorders. Unfortunately, the new donor-derived immune system may damage host cells (graft-versus-host disease (GvHD)), causing significant morbidity and mortality. Since regulatory T cells (Tregs) can modulate immune responses, it was hypothesised that Treg numbers in the haematopoietic stem cell grafts and/or peripheral blood may influence the development of GvHD and other transplant-related complications. In this project, a prospective observational clinical study of putative Tregs in human alloHSCT was performed in Oxford. Flow cytometry and methylation-specific qPCR assays were developed to quantify putative Tregs and lymphocyte populations within the grafts and post-transplant blood samples. Although low CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T-cell numbers were not associated with increased incidence of GvHD, low proportions of CD25(+)FOXP3(+)CD127(-/dim) cells in the graft (as a percentage of total CD4(+) T cells) were independently associated with poor engraftment, increased non-relapse mortality and inferior overall survival. Similarly, falling CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T-cell counts over the first three months post-transplant were associated with higher non-relapse mortality and inferior overall survival. In view of these novel findings, strategies that increase CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T cells in alloHSCT may improve clinical outcomes. One possible route for increasing Tregs is through cellular therapy. This project therefore tested the hypothesis that CD4(+)CD25(+)FOXP3(+) Tregs can be produced in vitro from conventional CD4(+) T cells. In the presence of TGFβ and Azacitidine, FOXP3 was expressed in the majority of activated CD4(+) T cells. These cells also had a demethylated FOXP3 TSDR enhancer which is specific to natural Tregs. However, most of these cells produced pro-inflammatory cytokines, for example, TNFα. Therefore, under these conditions, FOXP3 expression was not sufficient to produce a Treg phenotype. It is proposed that current focus for generating Tregs for human clinical trials should be directed towards improving isolation and expansion of ex vivo isolated Tregs.</p

Drugs, crime and methadone.

This paper seeks to examine the evidence of causal links between drug -misuse, particularly heroin, and criminal behaviour. While it is generally accepted that such a link*exists, the question is asked whether the treatment of drug misuse has an effect on levels of drug misuse and on criminal activity. The value of methadone treatment as one of several treatment modalities, is examined in this context. The author does not wish to advocate one form of treatment over another but merely to investigate what can be gained from a study of the literature

Microbial contributions to climate change through carbon cycle feedbacks

There is considerable interest in understanding the biological mechanisms that regulate carbon exchanges between the land and atmosphere, and how these exchanges respond to climate change. An understanding of soil microbial ecology is central to our ability to assess terrestrial carbon cycle–climate feedbacks, but the complexity of the soil microbial community and the many ways that it can be affected by climate and other global changes hampers our ability to draw firm conclusions on this topic. In this paper, we argue that to understand the potential negative and positive contributions of soil microbes to land–atmosphere carbon exchange and global warming requires explicit consideration of both direct and indirect impacts of climate change on microorganisms. Moreover, we argue that this requires consideration of complex interactions and feedbacks that occur between microbes, plants and their physical environment in the context of climate change, and the influence of other global changes which have the capacity to amplify climate-driven effects on soil microbes. Overall, we emphasize the urgent need for greater understanding of how soil microbial ecology contributes to land–atmosphere carbon exchange in the context of climate change, and identify some challenges for the future. In particular, we highlight the need for a multifactor experimental approach to understand how soil microbes and their activities respond to climate change and consequences for carbon cycle feedbacks