ABSTRACT
Regulatory T cell (Treg ) therapy has shown promise in early clinical trials for treating graft-versus-host disease, transplant rejection and autoimmune disorders. A challenge has been to isolate sufficiently pure Tregs and expand them to a clinical dose. However, there has been considerable progress in the development and optimization of these methods, resulting in a variety of manufacturing protocols being tested in clinical trials. In this review, we summarize methods that have been used to manufacture Tregs for clinical trials, including the choice of cell source and protocols for cell isolation and expansion. We also discuss alternative culture or genome editing methods for modulating Treg specificity, function or stability that could be applied to future clinical manufacturing protocols to increase the efficacy of Treg therapy.
Subject(s)
Cell- and Tissue-Based Therapy/methods , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer/methods , Cell Separation , Clinical Trials as Topic , Cryopreservation , Cytological Techniques , Epitopes , Gene Editing , Humans , Transplantation, Autologous , Transplantation, HomologousABSTRACT
Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.
Subject(s)
Inflammation/immunology , Intestines/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , Th1 Cells/cytology , Animals , Cell Adhesion , Cell Movement , Cell Proliferation , Chemokine CXCL10/metabolism , Epigenesis, Genetic , Female , Humans , Immune Tolerance , Immunosuppression Therapy , Integrins/metabolism , Interleukin-12/immunology , Male , Mice , Phenotype , Receptors, CCR/metabolism , Receptors, CXCR3/metabolism , Thymus Gland/immunologyABSTRACT
Health Board General Managers have overall responsibility for the efficiency, effectiveness and economy of the management of dental services within their area. In Scotland, six health boards cover islands with a total population of over 80,000. This article looks at the island areas in Scotland which have unique difficulties.
