We will study the """"""""initiation"""""""" of the elicitation of T cell mediated immunity in vivo. We have discovered that the initiation of elicitation is due to a series of processes. We postulate that these processes begin within hours after sensitization. We postulate that within 1-hr of immunization there is activation of Valpha14+ Jalpha18+ CD1d-restricted NKT cells. The NKT cells produce IL-4 to co-activate the Beta-1 Beta cell subset to produce initiating IgM antibodies. This, leads via local complement C5a activation of mast cells, to the local recruitment of effector T cells to the site of Ag challenge. These initiating processes occur in the murine model of allergic contact dermatitis, and in a related model of occupational asthma involving hapten elicitation of airway hyperreactivity (AHR) within 1-day of immunization. AHR similarly is postulated to depend on an early process mediated by NKT cell stimulated Beta-1 cell mediated C5a generation. Our focus in this proposal is the induction of CS-initiating Beta-1 cells. We propose this is due to prior rapid activation of NKT cells, perhaps via release endogenous glycolipid antigens, within hours post-contact immunization, to produce IL-4 that co-activates the Beta-1 cell, to produce the initiating IgM antibodies. Taken together, these studies extend the study of CS-initiation to induction of the mediating Beta-1 cells, potentially activated via NKT cell IL-4, and extend these concepts to mouse models of occupational medicine.
Specific Aim #1 : We will determine whether NKT cells are essential in CS, how they are activated, and if the NKT cells function in the initiation of CS by potentially producing IL-4.
Specific Aim #2 : We will determine if and how Beta-1 cells are activated by IL-4 early in the induction of CS, and whether IL-4, acting via STAT-6 signaling is essential, and how the Beta-1 cells may possibly migrate to lymph nodes and then to produce circulating CS-initiating IgM antibodies by only 1-day post-immunization.
Specific Aim #3 : In a hapten induced murine model of occupational asthma, we will determine the potential role of NKT cells in the production of B-1 cell derived IgM antibodies, that mediate C5a-dependent airway hyperreactivity (AHR); just 1-day post-immunization; and the mechanisms of the induced AHR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059801-04
Application #
7183609
Study Section
Special Emphasis Panel (ZRG1-ALY (02))
Program Officer
Minnicozzi, Michael
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$348,813
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Nazimek, Katarzyna; Bryniarski, Krzysztof; Askenase, Philip W (2016) Functions of Exosomes and Microbial Extracellular Vesicles in Allergy and Contact and Delayed-Type Hypersensitivity. Int Arch Allergy Immunol 171:1-26
Askenase, Phillip W; Bryniarski, Krzysztof; Paliwal, Vipin et al. (2015) A subset of AID-dependent B-1a cells initiates hypersensitivity and pneumococcal pneumonia resistance. Ann N Y Acad Sci 1362:200-14
Kawikova, Ivana; Askenase, Philip W (2015) Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res 1617:63-71
Majewska-Szczepanik, Monika; Paust, Silke; von Andrian, Ulrich H et al. (2013) Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-?, interferon-? and interleukin-12. Immunology 140:98-110
Bryniarski, Krzysztof; Ptak, Wlodzimierz; Jayakumar, Asha et al. (2013) Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J Allergy Clin Immunol 132:170-81
Dey, N; Szczepanik, M; Lau, K et al. (2011) Stimulatory lipids accumulate in the mouse liver within 30 min of contact sensitization to facilitate the activation of Naïve iNKT cells in a CD1d-dependent fashion. Scand J Immunol 74:52-61
Askenase, P W; Majewska-Szczepanik, M; Kerfoot, S et al. (2011) Participation of iNKT cells in the early and late components of Tc1-mediated DNFB contact sensitivity: cooperative role of ??-T cells. Scand J Immunol 73:465-77
Ptak, Wlodzimierz; Majewska, Monika; Bryniarski, Krzysztof et al. (2009) Epicutaneous immunization with protein antigen in the presence of TLR4 ligand induces TCR alpha beta+CD4+ T contrasuppressor cells that reverse skin-induced suppression of Th1-mediated contact sensitivity. J Immunol 182:837-50
Kerfoot, Steven M; Szczepanik, Marian; Tung, James W et al. (2008) Identification of initiator B cells, a novel subset of activation-induced deaminase-dependent B-1-like cells that mediate initiation of contact sensitivity. J Immunol 181:1717-27
Campos, Regis A; Szczepanik, Marian; Itakura, Atsuko et al. (2006) Interleukin-4-dependent innate collaboration between iNKT cells and B-1 B cells controls adaptative contact sensitivity. Immunology 117:536-47

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