Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction.
A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)-mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c(+ )APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E-dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.
Hessel
Edith M
EM
Dynavax Technologies, Berkeley, CA 94710, USA. ehessel@dvax.com
Chu
Mabel
M
Lizcano
Jennifer O
JO
Chang
Bonnie
B
Herman
Nancy
N
Kell
Sariah A
SA
Wills-Karp
Marsha
M
Coffman
Robert L
RL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D001491:Basophils / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007114:Immunization; D007073:Immunoglobulin E / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy; D015847:Interleukin-4 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D015533:Transcriptional Activation
D000276:Adjuvants, Immunologic; D000485:Allergens; D015703:Antigens, CD; D009838:Oligodeoxyribonucleotides; D015847:Interleukin-4; D007073:Immunoglobulin E