CPG-containing immunostimulatory DNA sequences elicit TNF-α-dependent toxicity in rodents but not in humans

被引：60

作者：

Campbell, John D. ^{[1
]}

Cho, Yan ^{[1
]}

Foster, Martyn L. ^{[2
]}

Kanzler, Holger ^{[1
]}

Kachura, Melissa A. ^{[1
]}

Lum, Jeremy A. ^{[1
]}

Ratcliffe, Marianne J. ^{[2
]}

Sathe, Atul ^{[1
]}

Leishman, Andrew J. ^{[2
]}

Bahl, Ash ^{[2
]}

McHale, Mark ^{[2
]}

Coffman, Robert L. ^{[1
]}

Hessel, Edith M. ^{[1
]}

机构：

[1] Dynavax Technol Corp, Berkeley, CA 94710 USA

[2] AstraZeneca Res & Dev Charnwood, Loughborough, Leics, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 09期

关键词：

PLASMACYTOID DENDRITIC CELLS; TOLL-LIKE RECEPTORS; ALLERGIC AIRWAY RESPONSES; COLONY-STIMULATING FACTOR; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; MAST-CELLS; MURINE MODEL; ALVEOLAR MACROPHAGES; LUNG INFLAMMATION;

D O I：

10.1172/JCI38294

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

CpG-containing immunostimulatory DNA sequences (ISS), which signal through TLR9, are being developed as a therapy for allergic indications and have proven to be safe and wen tolerated in humans when administrated via the pulmonary route. In contrast, ISS inhalation has unexplained toxicity in rodents, which express TLR9 in monocyte/macrophage lineage cells as well as in plasmacytoid DCs (pDCs) and B cells, the principal TLR9-expressing cells in humans. We therefore investigated the mechanisms underlying this rodent-specific toxicity and its implications for humans. Mice responded to intranasally administered 1018 ISS, a representative B class ISS, with strictly TLR9-dependent toxicity, including lung inflammation and weight loss, that was fully reversible and pDC and B cell independent. Knockout mouse experiments demonstrated that ISS-induced toxicity was critically dependent on TNF-alpha, with IFN-alpha required for TNF-alpha induction. In contrast human PBMCs, human alveolar macrophages, and airway-derived cells from Ascaris suum-allergic cynomolgus monkeys did not produce appreciable TNF-alpha in vitro in response to ISS stimulation. Moreover, sputum of allergic humans exposed to inhaled ISS demonstrated induction of IFN-inducible genes but minimal TNF-alpha induction. These data demonstrate that ISS induce rodent-specific TNF-alpha-dependent toxicity that is absent in humans and reflective of differential TLR9 expression patterns in rodents versus humans.

引用

页码：2564 / 2576

页数：13

共 52 条

[1] Deoxycytidyl-deoxyguanosine oligonucleotide classes A, B, and C induce distinct ctokine gene expression patterns in rhesus monkey peripheral blood mononuclear cells and distinct alpha interferon responses in TLR9-expressing rhesus monkey plasmacytoid dendritic cells [J].