TY  - BOOK
AU  - Umans, Jason G
TI  - In vitro induction of T regulatory cells by a methylated CpG DNA sequence in humans: Potential therapeutic applications in allergic and autoimmune diseases
SN  - 1088-5412
PY  - 2018///
KW  - *CD4-Positive T-Lymphocytes/im [Immunology]
KW  - *DNA/im [Immunology]
KW  - *Immunotherapy/mt [Methods]
KW  - *Lupus Erythematosus, Systemic/im [Immunology]
KW  - *T-Lymphocytes, Regulatory/im [Immunology]
KW  - Animals
KW  - Cattle
KW  - Cell Proliferation
KW  - Cells, Cultured
KW  - CpG Islands/ge [Genetics]
KW  - DNA Methylation/im [Immunology]
KW  - DNA/ge [Genetics]
KW  - Forkhead Transcription Factors/me [Metabolism]
KW  - Humans
KW  - Hypersensitivity/im [Immunology]
KW  - Hypersensitivity/th [Therapy]
KW  - Immunosuppression
KW  - Isoantigens/im [Immunology]
KW  - Lupus Erythematosus, Systemic/th [Therapy]
KW  - Lymphocyte Activation
KW  - Transforming Growth Factor beta/me [Metabolism]
KW  - MedStar Health Research Institute
KW  - Journal Article
N2  - BACKGROUND: Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25+ Forkhead box P3-positive (FOXP3+) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses; CONCLUSION: The use of this methylated CpG ODN offers a broad clinical application as a novel therapeutic method for Treg induction and, because of its low cost and small size, should facilitate delivery via nasal, respiratory, gastrointestinal routes, and/or by injection, routes of administration important for vaccine delivery to target sites responsible for respiratory, gastrointestinal, and systemic forms of allergic and autoimmune disease; METHODS: Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([3H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay; OBJECTIVE: The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [3H]-thymidine incorporation and promote FoxP3 expression in human CD4+ T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2); RESULTS: Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen-, mitogen-, and alloantigen-induced lymphoproliferation in vitro when measured by [3H]-thymidine. The synthetic methylated DNA CpG ODN but not an unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4+ T cells in the presence of TGF beta and IL-2. The induction of FoxP3+ suppressor cells is dose dependent and offers a potential clinical therapeutic application in allergic and autoimmune and inflammatory diseases
UR  - https://dx.doi.org/10.2500/aap.2018.39.4113
ER  -