The lung is constantly exposed to a variety of inhaled antigens and pathogens to which the immune system must respond. In particular, respiratory immune responses must be robust enough to eliminate respiratory pathogens, but must also be controlled enough so that the resulting inflammation does not interfere with lung function. A failure to achieve balance between immunity and inflammation leads to failed immunity and to a variety of idiopathic, progressive or chronic lung diseases. Understanding the mechanisms that keep pulmonary immunity and the associated inflammatory response in check, and yet prepared to respond quickly to potentially deadly or disease-causing pathogens is important to developing rational approaches to intervening in many pulmonary diseases. However, pulmonary immunology is an understudied area of lung research and little has been done to characterize the pulmonary immune system per se. Local lymphoid tissues, such as inducible Bronchus Associated Lymphoid Tissue (iBALT), are likely to play a central role in respiratory immune responses. However, the role of iBALT in respiratory immunity is poorly understood. Our preliminary data demonstrate that iBALT primes influenza-specific T and B cells in the absence of conventional lymphoid organs. Surprisingly, respiratory immune responses generated exclusively in iBALT lead to less morbidity and mortality, suggesting that iBALT may confer anti-inflammatory properties on local immune responses. In contrast, other studies correlate the presence of iBALT with the pathology associated with autoimmune disease or chronic respiratory infections. Thus, the role of iBALT in respiratory immunity remains enigmatic. Interestingly, respiratory inflammation in neonates appears to more efficiently elicit iBALT than inflammation in adults, suggesting that there is a developmental window for the formation of iBALT. We will test the hypothesis that the formation of iBALT in neonates will permanently change the architecture and function of the lung and that these changes will be manifest as (i) altered sensitivity to respiratory antigens, (ii)changes in the number, phenotype and migratory habits of dendritic cells in the lung, (iii)changes in T cell responses to respiratory antigens and (iv) changes in the outcome of immune responses to respiratory antigens and pathogens. These experiments will lead to a new understanding of how iBALT functions in respiratory immunity. Relevance to human health. The results from these experiments will lead to a new understanding of how iBALT functions in respiratory immunity to innocuous antigens and to pathogens of the respiratory tract. We expect that the results from these experiments will help to develop therapies that take advantage of the beneficial properties of iBALT (by promoting immunie responses to pathogens) and prevent iBALT from exacerbating respiratory pathology (asthma and chronic inflammatory diseases of the lung).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL069409-09
Application #
7807755
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Colombini-Hatch, Sandra
Project Start
2001-09-30
Project End
2010-12-31
Budget Start
2009-06-01
Budget End
2009-12-31
Support Year
9
Fiscal Year
2009
Total Cost
$373,835
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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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