Mechanism of Action of Inhibition of Allergic Immune Responses

Mechanism of Action of Inhibition of Allergic Immune Responses by a Novel Antedrug TLR7 Agonist 

Hiroyuki Matsui*, Hideyuki Tomizawa*, Kazuo Eiho*, Yasuo Kashiwazaki*, Susan Edwards†, Mark Biffen†, John P. Bell†, Ashwani Bahl†, Andrew J. Leishman†, Clare M. Murray†, Haruo Takaku* and Yutaka Ueda

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Address correspondence and reprint requests to Hiroyuki Matsui, Dainippon Sumitomo Pharma Co., Ltd., 1-98, Kasugadenaka 3 Chome, Konohana-ku, Osaka 554-0022, Japan. E-mail address: [e-mail]

Abstract

Triggering innate immune responses through TLRs is expected to be a novel therapeutic strategy for the treatment of allergic diseases. TLR agonists are able to modulate Th2 immune responses through undefined mechanisms. We investigated the mechanism of action of the suppression of Th2 immune responses with a novel antedrug TLR7 agonist. The antedrug is rapidly metabolized by plasma esterases to an acid with reduced activity to limit systemic responses. Topical administration of this compound inhibited features of the allergic airway inflammatory response in rat and murine allergic airways model. Type I IFN played a role in the suppression of Th2 cytokines produced from murine splenocytes. Inhibition of Th2 immune responses with the antedrug TLR7 agonist was shown to be via a type I IFN–dependent mechanism following short-term exposure to the compound, although there might be type I IFN–independent mechanisms following long-term exposure. We have demonstrated that local type I IFN signaling and plasmacytoid dendritic cells, but not Th1 immune responses, are required for in vivo efficacy against murine airway Th2-driven eosinophilia. Furthermore, migration of dendritic cell subsets into the lung was related to efficacy and is dependent on type I IFN signaling. Thus, the mechanism of action at the cytokine and cellular level involved in the suppression of Th2 allergic responses has been characterized, providing a potential new approach to the treatment of allergic disease.

*Author AffiliationsPharmacology Research Laboratory, Dainippon Sumitomo Pharma Co., Ltd., Osaka 541-0045, Japan; andBioscience, AstraZeneca Research and Development Charnwood, Loughborough, Leicestershire LE11 5RH, United Kingdom

مقاله جدید( 2012)

Glutamine Suppresses Airway Neutrophilia by Blocking Cytosolic Phospholipase A2 via an Induction of MAPK Phosphatase-1

1. Chang-Hoon Lee*,
2. Hae-Kyoung Kim*,
3. June-Mo Kim*,
4. Otgonzaya Ayush*,
5. Suhn-Young Im†,
6. Dae-Kyu Oh‡,1 and
7. Hern-Ku Lee*,1

1. ^*Department of Immunology, Chonbuk National University Medical School, Jeonju, Chonbuk 561-182, Republic of Korea;
2. ^†Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju 500-757, Republic of Korea; and
3. ^‡Department of Preventive Medicine, Gachon University of Medicine and Science, Incheon 406-799, Republic of Korea

1. Address correspondence and reprint requests to Dr. Hern-Ku Lee, Department of Immunology, Chonbuk National University Medical School, Jeonju, Chonbuk 561-182, Republic of Korea. E-mail address: [e-mail]

1. ↵1 D.-K.O. and H.-K.L. contributed equally to this work.

Abstract

Neutrophils are inflammatory cells that may contribute in a crucial way to the pathophysiology of steroid-resistant severe asthma. We previously reported that the nonessential amino acid l-glutamine (Gln) suppressed the recruitment of neutrophils into the airway in a murine model of asthma. In this study, we investigated the mechanisms by which Gln exerts beneficial effects in airway neutrophilia. We used the model we previously developed, which is suitable for examining sequential early asthmatic events, including neutrophil infiltration. Gln suppressed airway neutrophilia in a CXC chemokine-independent way. Airway neutrophilia was associated with cytosolic phospholipase A₂ (cPLA₂) and 5-lipoxygenase (5-LO) activities. p38 MAPK, the upstream pathway of cPLA₂ and 5-LO, played a key role in inducing airway neutrophilia. Gln inhibited not only the phosphorylation of cPLA₂ and p38 MAPK but also leukotriene B₄ levels in the airways. Gln induced the early induction of MAPK phosphatase-1 (MKP-1) protein, a negative regulator of p38. MKP-1 small interfering RNA abrogated all the effects of Gln. Our results suggest that pathways involving p38/cPLA₂/5-LO have a major role in airway neutrophilia. Gln suppresses airway neutrophilia via inhibiting p38 MAPK and its downstream pathways in an MKP-1–dependent way, which may provide a novel therapeutic strategy for pulmonary neutrophilic inflammatory diseases.

بهار میخاد زودتربیاد

Unlinked Memory Helper Responses Promote Long-Lasting Humoral Al

Essential help for long-lived alloantibody responses is theoretically provided only by CD4 T cells that recognize target alloantigen, processed and presented by the allospecific B cell. We demonstrate that in an alloresponse to multiple MHC disparities, cognate help for class-switched alloantibody may also be provided by CD4 T cells specific for a second “helper” alloantigen. This response was much shorter-lived than when help was provided conventionally, by Th cell recognition of target alloantigen. Nevertheless, long-lasting humoral alloimmunity developed when T cell memory against the helper alloantigen was first generated. Costimulatory blockade abrogated alloantibody produced through naive Th cell recognition of target alloantigen but, crucially, blockade was ineffective when help was provided by memory responses to the accessory helper alloantigen. These results suggest that memory Th cell responses against previously encountered graft alloantigen may be the dominant mechanism for providing help to generate new specificities of alloantibody in transplant patients receiving immunosuppression.