Abstract | 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. OBJECTIVE: 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. 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. 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.
|
Authors | Oliver J Lawless, Joseph A Bellanti, Milton L Brown, Kathryn Sandberg, Jason G Umans, Li Zhou, Weiqian Chen, Julie Wang, Kan Wang, Song Guo Zheng |
Journal | Allergy and asthma proceedings
(Allergy Asthma Proc)
Vol. 39
Issue 2
Pg. 143-152
(Mar 01 2018)
ISSN: 1539-6304 [Electronic] United States |
PMID | 29490770
(Publication Type: Journal Article)
|
Chemical References |
- FOXP3 protein, human
- Forkhead Transcription Factors
- Isoantigens
- Transforming Growth Factor beta
- DNA
|
Topics |
- Animals
- CD4-Positive T-Lymphocytes
(immunology)
- Cattle
- Cell Proliferation
- Cells, Cultured
- CpG Islands
(genetics)
- DNA
(genetics, immunology)
- DNA Methylation
(immunology)
- Forkhead Transcription Factors
(metabolism)
- Humans
- Hypersensitivity
(immunology, therapy)
- Immunosuppression Therapy
- Immunotherapy
(methods)
- Isoantigens
(immunology)
- Lupus Erythematosus, Systemic
(immunology, therapy)
- Lymphocyte Activation
- T-Lymphocytes, Regulatory
(immunology)
- Transforming Growth Factor beta
(metabolism)
|