Influenza causes significant morbidity and mortality in hematopoietic cell transplantation (HCT) recipients, who are immunocompromised. Vaccination is the most effective way of preventing influenza but is less effective in immunocompromised patients than in healthy individuals. Thus, there is a need to understand the mechanisms underlying poor vaccine responses as well as establish biomarkers of immune competence. We surmise that understanding the relationships between antigen presenting cells (including monocytes and DCs), influenza-specific CD4+ T cells and antibody responses elicited by vaccination may enable a more rational design of vaccination strategies and timing in this group of patients. All studies to date have shown diminished CD4+ T cell numbers and proliferative T cell responses even at 12 months post transplant. We will utilize a systems biology analysis to define the immune alteration underlying the diminished responses to influenza vaccines in this group of patients. This will form a ground for development of new immuneenhancing strategies. We will focus on systems biology analysis of three cellular compartments that are essential for the generation and the quality of antibody responses to vaccines - the inducers (dendritic cells/monocytes and their subsets);regulators (T follicular helper cells - Tfh), and effectors (B cells). To date, there are no studies describing a systematic and comprehensive analysis of the reconstitution of these three blood compartments in patients who have undergone autologous HCT. Moreover, Tfh immune reconstitution after transplant (allogeneic or autologous) has not been examined for the identification of these cells until very recently. The alteration(s) in either or all of these compartments will have an impact on the quality of flu vaccine responses after HCT. Thus, our study presents an opportunity to analyze, at a systems level, the responses to flu vaccine in patients who have undergone HCT.
Three aims are proposed:
AIM 1 : To establish the cellular and transcriptional signatures of response to flu vaccination in patients who underwent autologous HCT and in age-matched healthy volunteers.
AIM 2 : To establish the kinetics of blood DC subsets, Tfh and B cell compartments reconstitution in patients who underwent autologous HCT.
AIM 3 : To establish the functional competence of blood DC subsets and Tfh cells in patients who underwent autologous HCT.

Public Health Relevance

People who have bone marrow transplants are susceptible to numerous diseases due to their immunocompromised state. Compounding this is the fact that their immune system doesn't induce strong protective innmunity upon vaccination. This project will use a systems biology approach to examine the immune responses in these patients after vaccination with the goal of improving vaccines strategies for these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI089987-04
Application #
8501330
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$356,360
Indirect Cost
$78,746
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
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