Medical Student Research Fellowship for Summer 2006

Mentor: Michelle Gill
Department: Pediatrics
Room number: J4.126
Mail Code: 9063
Phone number: 214-648-3720
E-mail: Michelle.Gill@UTSouthwestern.edu
Project title: Immune Cell Activation in Patients with Allergic Asthma

Human subjects IRB approved project number (where applicable): #042006-018

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Patient-based research

Brief Description of Project:

Asthma, a chronic disease of the airways, is the leading cause of hospitalization of children at Children's Medical Center of Dallas. Population studies indicate that the prevalence of asthma is increasing. While there are many options for asthma management, including the use of inhaled corticosteroid medications, no therapy is curative and many are ineffective. The role of the immune system in the pathogenesis of asthma has been widely studied, but remains poorly understood, especially in children. By defining how the individual immune cell subsets are affected in the respiratory tract and blood of children with asthma, we will increase our understanding of how the immune system is affected by this disease.
Dendritic cells comprise an important subset of immune cells that are responsible for initiating and directing immune responses. They accomplish this through interactions with other immune cells, including T cells, B cells, and basophils. Dendritic cells have been shown to play important roles in mediating various human diseases, including allergic conditions, autoimmune diseases such as lupus, and even cancer. In simple terms, dendritic cells represent the general of the immune system army and many processes of abnormal immune system function can be partially attributed to dendritic cell dysfunction. Since asthma represents a dysregulation of immune system processes, it therefore follows that dendritic cells could be contributing to this disease. Although the pathogenesis of asthma has been studied by many scientists and pediatricians alike, there are few studies investigating the involvement of dendritic cells in pediatric asthma. Thus, we propose to study how the numbers, activation status, and function of dendritic cells and other immune cells from pediatric subjects with asthma differ from those in healthy subjects. Additionally, we will study whether these cells are recruited into the respiratory tract of subjects with asthma, where they could potentially mediate airway abnormalities associated with asthma.IgE (immunoglobulin E) has been demonstrated to play a role in the pathogenesis of allergic asthma . Fc?RI is the receptor for IgE, and is present on the surface of basophils, monocytes, and dendritic cells. Thus, the amount/level of Fc?RI on these cell types will likely be elelvated in subjects with asthma and represent potential future targets for immunomodulatory treatment studies.

In this study, we will investigate the respiratory tract cellular immune status in patients with allergic asthma. By defining the number and types of immune cells (and specifically dendritic cells) and the chemical messengers in both the respiratory secretions and the blood of patients with asthma and comparing them with healthy control subjects, we hope to define specific cellular immune system aberrations associated with allergic asthma. To insure that our results do not reflect the effect of respiratory viruses, we will perform tests to detect the presence of respiratory viruses on each participant. We also expect that the results will contribute to future development of potential preventative and/or therapeutic strategies for patients with allergic asthma.

Previous Research Activities or Publications with Medical Students:

Kristin Long worked for our laboratory at UTSW prior to entering medical school. Below is an abstract (recently presented at the annual Pedatric Academic Society meeting in San Francisco, CA, April 30 - May 2, 2006) summarizing her previous work.

Title: Differences in Mucosal Antigen Presenting Cell (APC) Recruitment in Children with Respiratory Syncytial Virus (RSV) and Influenza (Flu)
Michelle Gill, MD/PhD1,2, Jacques Banchereau, PhD2, Kristin Long1, Theresa Kwon, MD1, Asuncion Mejias MD1, John Connolly, PhD2, Lonnie Roy, PhD3 and Octavio Ramilo, MD1. 1Pediatrics, UT Southwestern Medical Center, Dallas, Texas, United States; 2Baylor Institute for Immunology Research, Dallas, TX, United States and 3Children's Medical Center of Dallas, Dallas, TX, United States.
Background: RSV is the major cause of bronchiolitis in infants and young children.Yet, many aspects of its immunopathogenesis remain undefined. Flu is also a significant respiratory pathogen in infants and children. While RSV and Flu both cause respiratory disease in children, there are notable differences between these pathogens.
Objective: We previously reported myeloid dendritic cell (mDC) recruitment to the respiratory mucosa in pts with RSV. We next compared mDC, monocyte, and T cell recruitment in pts with RSV and Flu, hoping to uncover differences in the early immune response to these viruses.
Design/Methods: Patients (pts) under 36 months old requiring hospitalization for RSV or Flu were enrolled. Pts with no respiratory symptoms were enrolled as controls. Blood and nasal wash (NW) specimens were collected, stained with fluorochrome-labeled monoclonal antibodies directed against mDCs, monocytes, and T cells and analyzed by flow cytometry. Conc. of several NW cyto/chemokines were analyzed by Luminex XMAP technology. Data were analyzed with Kruskal-Wallis tests followed by post-hoc pair-wise comparisons.
Results: Flu resulted in greater of mDCs and monocytes recruitment to the NW than RSV (p<0.003). Median NW mDCs were 10,880 in Flu, 3040 in RSV, and 177 in controls. Median NW monocytes: 299,430 in Flu, 73,640 in RSV, and 36,051 in controls. RSV and Flu pts had less blood mDCs than controls (p<0.003). Blood monocytes were not lower in Flu or RSV pts than controls. Blood and NW CD4 and CD8 T cell numbers were similar in all groups. NW MCP-1 was higher in Flu (380 pg/ml) compared with RSV (86 pg/ml;p<0.006) and controls(47pg/ml:p<0.003). NW IL-6, IL-8, MIP1-a, IP-10, and TNF-a conc. were higher in RSV and Flu pts than controls (p<0.05) but were not different from each other.
Conclusions: Flu infection results in greater recruitment of mDCs and monocytes to the nasal mucosa than RSV. Increased concentration of NW MCP-1 in Flu pts may contribute to this difference. Further study of how Flu and RSV differentially effect APC recruitment and function will enhance our understanding of the ensuing immune responses to these viruses.

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