Control of in vitro immune responses by regulatory oligodeoxynucleotides through inhibition of pIII promoter directed expression of MHC class II transactivator in human primary monocytes.

Abstract

Ag presentation is a key step in the initiation of adaptive immune responses that depends on the expression of MHC Ags and costimulatory molecules. Immune-enhancing CpG and non-CPG oligodeoxynucleotides (ODNs) stimulate Ag presentation by stimulating the expression of these molecules and by promoting dendritic cell maturation. In this report, we identify immunoregulatory orthophosphorothioate non-CpG molecules, referred to as regulatory ODNs (rODNs), by their ability to inhibit allogeneic monocyte-stimulated T cell responses and down-regulate HLA-DR in human primary monocytes. The rODNs promoted the survival of macrophages and were able to activate IL-8 secretion through a chloroquine-resistant pathway. Messenger RNAs for HLA-DR alpha and beta and the MHC CIITA were reduced by rODNs but not by stimulatory CpG ODN2006 and non-CpG ODN2006a. CIITA transcription in monocytes was controlled primarily by promoter III and not by promoter I or IV. rODNs blocked promoter III-directed transcription of CIITA in these cells. Under conditions that induced dendritic cell differentiation, rODNs also reduced HLA-DR expression. The activity of rODNs is phosphorothioate chemistry and G stretch dependent but TLR9 independent. G tetrads were detected by circular dichroism in active rODNs and associated with high m.w. multimers on nondenaturing gels. Heat treatment of rODNs disrupted G tetrads, the high m.w. aggregates, and the HLA-DR inhibitory activity of the ODNs. The inhibition of immune responses by regulatory oligodeoxynucleotides may be useful for the treatment of immune-mediated disorders including autoimmune diseases and graft rejection.

• Authors: Jinhai Wang, Gregory Roderiquez, Taneishia Jones, Peter McPhie, Michael A Norcross
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 1 Pg. 45-52 (Jul 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17579020 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• CPG-oligonucleotide
• Growth Inhibitors
• HLA-DR Antigens
• HLA-DR alpha-Chains
• Isoantigens
• MHC class II transactivator protein
• Nuclear Proteins
• Oligodeoxyribonucleotides
• Trans-Activators

Topics

• Adjuvants, Immunologic (pharmacology)
• Cell Proliferation
• Cells, Cultured
• Down-Regulation (immunology)
• Growth Inhibitors (physiology)
• HLA-DR Antigens (biosynthesis, metabolism)
• HLA-DR alpha-Chains
• Humans
• Isoantigens (pharmacology)
• Monocytes (immunology, metabolism)
• Nuclear Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Oligodeoxyribonucleotides (pharmacology)
• Promoter Regions, Genetic (genetics, immunology)
• T-Lymphocytes (cytology, immunology)
• Trans-Activators (antagonists & inhibitors, biosynthesis, genetics)
• Transcription, Genetic (immunology)