The respiratory tract faces unique immunologic demands. Since excessive immune or inflammatory responses can be as damaging to the lung as uncontrolled infection, it is thought that the respiratory tract has developed mechanisms that keep the pulmonary immune system and the associated inflammatory response in check, yet prepared to respond quickly to potentially deadly or disease-causing materials. Understanding these mechanisms is important for developing knowledge-based approaches to intervene in many pulmonary diseases. In order to separate those aspects of respiratory immunity that are determined locally from those that are determined at systemic sites, we examined respiratory immune responses in mice that lacked all encapsulated lymph nodes (LNs), Peyer?s patches and spleen, but retained the nasal associated lymphoid tissue (NALT), as well as the interstitial lymphoid areas of the lung. Using these mice, we demonstrated that the respiratory tract can perform many immune functions in the complete absence of conventional lymphoid organs. Furthermore, we showed that the NALT and the lymphoid areas of the lung are formed by mechanisms that bypass the lymphotoxin-a signaling pathway, which is required for the development of all encapsulated lymphoid organs. In light of our preliminary data, we hypothesize that respiratory immune responses can be initiated directly in the respiratory tract by novel mechanisms and that these mechanisms regulate respiratory immunity and accommodate the special needs of the respiratory system. To test this hypothesis, we propose to define in Aim 1 whether immune responses generated directly in the NALT and/or lung result in effective immunity to primary or secondary challenge, to determine in Aim 2 whether cellular immune responses generated in the NALT and/or lung differ in the absence of conventional lymphoid tissues, to determine in Aim 3 how humoral immune responses in the respiratory tract differ in the absence of conventional lymphoid tissues, and to determine in Aim 4 the molecular mechanisms that control the recruitment and organization of naive lymphocytes in the lung. Together, these experiments will clarify the immune functions of NALT as well as the interstitial lymphoid areas in the lung, and will identify those aspects of respiratory immunity that are specific to these tissues. The knowledge gained by these experiments will facilitate the rational design of protective or therapeutic strategies targeted to these tissues to control pulmonary diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL069409-01
Application #
6441192
Study Section
Special Emphasis Panel (ZHL1-CSR-P (S1))
Program Officer
Musson, Robert
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$432,500
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Meza-Perez, Selene; Randall, Troy D (2017) Immunological Functions of the Omentum. Trends Immunol 38:526-536
Munguía-Fuentes, Rosario; Yam-Puc, Juan Carlos; Silva-Sánchez, Aarón et al. (2017) Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult. Front Immunol 8:13
Nellore, Anoma; Randall, Troy D (2016) Narcolepsy and influenza vaccination-the inappropriate awakening of immunity. Ann Transl Med 4:S29
Hwang, Ji Young; Randall, Troy D; Silva-Sanchez, Aaron (2016) Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung. Front Immunol 7:258
León, Beatriz; Bradley, John E; Lund, Frances E et al. (2014) FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 5:3495
Randall, T D; Mebius, R E (2014) The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol 7:455-66
Randall, Troy D; Kern, Jeffrey A (2014) Tertiary lymphoid structures target the antitumor immune response to lung cancer. Am J Respir Crit Care Med 189:767-9
Ballesteros-Tato, André; León, Beatriz; Lee, Byung O et al. (2014) Epitope-specific regulation of memory programming by differential duration of antigen presentation to influenza-specific CD8(+) T cells. Immunity 41:127-40
Ballesteros-Tato, André; Randall, Troy D (2014) Priming of T follicular helper cells by dendritic cells. Immunol Cell Biol 92:22-7
Johnston, Carl J; Manning, Casey M; Rangel-Moreno, Javier et al. (2013) Neonatal irradiation sensitizes mice to delayed pulmonary challenge. Radiat Res 179:475-84

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