Antigen-specific peripheral tolerance induced by topical application of NF-kappaB decoy oligodeoxynucleotide.
Activation and maturation of dendritic cells (DC) are crucial for the establishment of delayed-type hypersensitivity (DTH). However, antigen presentation by immature DC (iDC) might lead to antigen-specific peripheral tolerance. NF-kappaB plays significant roles in upregulation of co-stimulatory molecules and cytokines in DC and therefore we investigated whether NF-kappaB decoy oligodeoxynucleotide (ODN) might induce tolerance to DTH. NF-kappaB decoy ODN suppressed ovalbumin (OVA)-induced DTH responses not only in naïve but also in presensitized mice. The suppressive effect was found to be antigen-specific. NF-kappaB decoy ODN-induced tolerance involved CD4(+)CD25(+) regulatory T cells (Treg), because in vivo depletion of CD25(+) T cells abrogated the tolerance, whereas adoptive transfer of such T cell population from tolerant mice induced tolerance. Furthermore, the induction of Treg was related to insufficient migration and/or maturation of DC, because a sizable DC population still remained in peripheral tissue even after exposure to exogenous antigen in NF-kappaB decoy ODN-treated mice. Even if they migrated into lymph nodes, they showed insufficient upregulation of co-stimulatory molecules and impaired antigen-specific activation of T cells. Topical application of NF-kappaB decoy ODN might thus be a new approach to induce antigen-specific peripheral tolerance.
Isomura
Iwao
I
Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Tsujimura
Kunio
K
Morita
Akimichi
A
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control*; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009824:Ointments; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010047:Ovalbumin / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D012867:Skin / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D015704:CD4 Antigens; C468119:NF-kappaB decoy; D009824:Ointments; D009838:Oligodeoxyribonucleotides; D015375:Receptors, Interleukin-2; D010047:Ovalbumin