Asthma and allergic diseases are important health concerns, and mast cells and possibly basophils are the major effector cells of IgE-mediated immediate hypersensitivy in humans. Previous work by the investigators involved in Project 1 includes developing tryptase as a clinical marker for mast cell activation;finding activation of mast cells in the asthmatic airway and during systemic anaphylaxis;identifying two types of human mast cells (MC{T} and MC{TC}) based on the protease content of their secretory granules and the surface expression of CD88;discovering the activating form of FcyRII, CD32a, constitutively expressed on the surface of skin MC{TC} cells;and finding Syk-deficiency in basophils with the non-releaser phenotype and in mast cells after antigen desensitization in vitro. The three specific aims of the current project are to: 1. Test the hypothesis that human mast cells and basophils in vitro undergo cross-desensitization to different antigens and heterologous desensitization through FceRI and FcvRlla. Indeed, preliminary data suggest that when mast cells of the MC{TC} type are IgE anti-DNP-sensitized and then desensitized with low doses of DNP-BSA, both cross-desensitization and heterologous desensitization occurs. 2. Explore in vitro the mechanism(s) for desensitization of human mast cells involving Src and/or Syk tyrosine kinases. Although Syk depletion seems likely, the involvement of Lyn and/or Fyn is uncertain. Further, the possibility that subcellular compartmentalization of signaling differs for desensitization and activation will be examined. Collaborations with Project 3 on studies of Lyn kinase involvement in desensitization, and with Project 4 on the involvement of sphingosine kinase-1 in desensitization of human mast cells and basophils facilitate these mechanistic studies. 3. Determine whether penicillin desensitization of human subjects in vivo produces antigen cross-desensitization of mast cells and basophils and depletes Syk from peripheral blood basophils. This clinical study will begin to translate our in vitro findings to the in vivo situation. Clinical tolerance due to desensitization can be distinguished from that due to immunotherapy by its rapid induction (hours) and short persistence (days) once allergen administration ceases. We hypothesize that desensitization targets primarily mast cells and basophils. Understanding more precisely the characteristics of and the mechanism(s) behind desensitization will enable physicians to better utilize this approach to reduce mast cell/basophil-mediated contributions to asthma and allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI077435-05
Application #
8375530
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$341,966
Indirect Cost
$128,076
Name
Virginia Commonwealth University
Department
Type
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Oyeniran, Clement; Sturgill, Jamie L; Hait, Nitai C et al. (2015) Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice. J Allergy Clin Immunol 136:1035-46.e6
Oskeritzian, Carole A; Hait, Nitai C; Wedman, Piper et al. (2015) The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses. J Allergy Clin Immunol 135:1008-18.e1
Kim, Eugene Y; Sturgill, Jamie L; Hait, Nitai C et al. (2014) Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching. FASEB J 28:4347-58
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Lyons, Jonathan J; Sun, Guangping; Stone, Kelly D et al. (2014) Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J Allergy Clin Immunol 133:1471-4
Le, Quang Trong; Lotfi-Emran, Sahar; Min, Hae-Ki et al. (2014) A simple, sensitive and safe method to determine the human ?/?-tryptase genotype. PLoS One 9:e114944
Morales, Johanna K; Saleem, Sheinei J; Martin, Rebecca K et al. (2014) Myeloid-derived suppressor cells enhance IgE-mediated mast cell responses. J Leukoc Biol 95:643-50
Martin, Rebecca K; Saleem, Sheinei J; Folgosa, Lauren et al. (2014) Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells. J Leukoc Biol 96:151-9
Liang, Jie; Nagahashi, Masayuki; Kim, Eugene Y et al. (2013) Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23:107-20
Nagahashi, Masayuki; Kim, Eugene Y; Yamada, Akimitsu et al. (2013) Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network. FASEB J 27:1001-11

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