Author Correction: Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Regulatory T cells: tolerance induction in solid organ transplantation.

The concept of regulatory T cell (Treg ) therapy in transplantation is now a reality. Significant advances in science and technology have enabled us to isolate human Tregs , expand them to clinically relevant numbers and infuse them into human transplant recipients. With several Phase I/II trials under way investigating Treg safety and efficacy it is now more crucial than ever to understand their complex biology. However, our journey is by no means complete; results from these trials will undoubtedly provoke both further knowledge and enquiry which, alongside evolving science, will continue to drive the optimization of Treg therapy in the pursuit of transplantation tolerance. In this review we will summarize current knowledge of Treg biology, explore novel technologies in the setting of Treg immunotherapy and address key prerequisites surrounding the clinical application of Tregs in transplantation.

Microbiota, immunity and the liver.

The gut harbors a complex community of over 100 trillion microbial cells known to exist in symbiotic harmony with the host influencing human physiology, metabolism, nutrition and immune function. It is now widely accepted that perturbations of this close partnership results in the pathogenesis of several major diseases with increasing evidence highlighting their role outside of the intestinal tract. The intimate proximity and circulatory loop of the liver and the gut has attracted significant attention regarding the role of the microbiota in the development and progression of liver disease. Here we give an overview of the interaction between the microbiota and the immune system and focus on their convincing role in both the propagation and treatment of liver disease.

Humanized Mice as Preclinical Models in Transplantation.

Animal models have been instrumental in our understanding of the mechanisms of rejection and the testing of novel treatment options in the context of transplantation. We have now entered an exciting era with research on humanized mice driving advances in translational studies and in our understanding of the function of human cells in response to pathogens and cancer as well as the recognition of human allogeneic tissues in vivo. In this chapter we provide a historical overview of humanized mouse models of transplantation to date, outlining the distinct strains and share our experiences in the study of human transplantation immunology.

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora.

Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation.

Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model.

Promoting transplantation tolerance; adoptive regulatory T cell therapy.

Transplantation is a successful treatment for end-stage organ failure. Despite improvements in short-term outcome, long-term survival remains suboptimal because of the morbidity and mortality associated with long-term use of immunosuppression. There is, therefore, a pressing need to devise protocols that induce tolerance in order to minimize or completely withdraw immunosuppression in transplant recipients. In this review we will discuss how regulatory T cells (T(regs)) came to be recognized as an attractive way to promote transplantation tolerance. We will summarize the preclinical data, supporting the importance of these cells in the induction and maintenance of immune tolerance and that provide the rationale for the isolation and expansion of these cells for cellular therapy. We will also describe the data from the first clinical trials, using T(regs) to inhibit graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation and will address both the challenges and opportunities in human T(reg) cell therapy.

Regulatory T cells in bronchial asthma.

The main focus of this review was the role of a specific subset of T cells with immunomodulatory or immunosuppressive activities, termed regulatory T cells (Tregs), in the pathogenesis and treatment of bronchial asthma. Evidence that these cells are important in maintaining immune homeostasis in health and exhibit impaired activity in active disease will be discussed. Their therapeutic potential is perhaps best highlighted by evidence that therapies with demonstrated efficacy in allergic and asthmatic disease are associated with the induction or restoration of regulatory T-cell function, e.g. glucocorticoids, allergen immunotherapy. Strategies to improve the safety and efficacy of these treatments and that induce or boost Tregs in bronchial asthma are discussed.