Date

June 2012

Document Type

Thesis

Degree Name

M.P.H.

Department

Dept. of Public Health and Preventive Medicine

Institution

Oregon Health & Science University

Abstract

BACKGROUND: Recent research indicates that CD8+ T cells play a critical role in the management of Mycobacterium tuberculosis (Mtb) infections and do so, in part, through an ability to detect and respond to changes in bacillary burden. Consequently, the development of TB vaccines and diagnostic tests intended for use within high prevalence populations can be aided by the identification of CD8+ T cell immunodominant Mtb antigens and epitopes—particularly those that differentiate between active and latent TB phenotypes. OBJECTIVE: This study tests the hypothesis that, among TB positive subjects from a high prevalence region, CD8+ T cell IFN-γ response to novel CD8+ T cell-associated Mtb antigens will be positively associated with active disease. DATA & METHODS: Five novel antigens that were hypothesized to have LTBI specificity were selected via an IFN-γ CD8+ T cell screening process from among the Large-Scale Antigen Discovery Program’s (LSADP) 38,617-element Mtb genomic peptide library. Candidates were then screened in a cross-sectional clinical validation study wherein antigen-induced IFN-γ CD8+ T cell responses were measured, via ELISPOT, for 52 ATB and 56 LTBI subjects in Kampala, Uganda. A previously validated conservative threshold for determining positive vs. negative IFN-γ CD8+ T cell response was defined, a priori, as: Mtb Antigen-elicited Spot Forming Units (SFUs) minus two times the background SFU standard deviation minus ten SFUs. TB phenotype was determined clinically, based on WHO TB diagnostic criteria. Data related to potential confounding and effect-modifying factors were extracted from household- and individual-level surveys and clinical records. Unadjusted and adjusted odds ratios for IFN-γ CD8+ T cell response by TB phenotype were estimated using univariate and multivariate regression modeling. RESULTS: Examination of univariate statistics showed that subjects did not differ by age or sex according to either TB phenotype or IFN-γ CD8+ T cell response. Using the predefined cut point, neither univariate nor multivariate analyses demonstrated a statistically significant association between IFN-γ CD8+ T cell response and TB phenotype for individual antigens or the five antigen set as a whole (OR=0.64, p= 0.24). However, quantitative antigen specific INF-γ production was significantly associated with active tuberculosis for four of five antigens. Specifically, a statistically significant increase in IFN-γ CD8+ T cell response of 24.8-27.1 spot forming units was observe among ATB vs. LTBI subjects (0.001 ≤ p ≤ 0.015). CONCLUSIONS: Continuous CD8+ T cell IFN-γ responses to four out of five novel Mtb antigens demonstrate a positive relationship between CD8+ T cell response and elevated bacillary burden.

Identifier

doi:10.6083/M4BG2M0Z

School

School of Medicine

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