Immune-Based Latent TB Detection via T-Cell Segmentation
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Solution Overview
Problem
Current methods for identifying latent tuberculosis (TB) infection status and determining the risk of progression to active TB are inadequate, as they lack specificity and sensitivity, particularly in BCG-vaccinated individuals and those who are immunocompromised. Additionally, there is no direct test to measure mycobacterial pathogen load, leading to unnecessary invasive and costly diagnostic procedures.
Innovation Solution
An immune-based test that involves providing a sample of T-cells, exposing them to TB antigens, identifying CD4-positive T-cells that secrete IFN-γ, and determining the percentage of HLA-DR-positive cells among these T-cells. This test can be used to determine latent TB infection status and identify individuals at higher risk of progressing to active TB.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If TST or IGRA tests are used to identify LTBI, then LTBI status can be determined, but the tests lack specificity and sensitivity particularly in BCG-vaccinated individuals and immunocompromised patients
Solution Approach 1:
The patent segments the immune response measurement into distinct T-cell subsets (CD4+, CD8+) and further segments by activation markers (HLA-DR, CD38, Ki-67) and cytokine production (IFN-γ, TNF-α). This multi-level segmentation allows differentiation of recent from remote infections and improves detection accuracy in challenging populations where traditional tests fail.
Solution Approach 2:
The patent changes the measurement parameters from simple presence/absence of immune response (TST/IGRA) to quantitative assessment of multiple parameters including T-cell frequency, activation marker expression levels, cytokine production capacity, and temporal dynamics. This parameter expansion enables precise risk stratification and overcomes the limitations of binary test results.
2Reliability
If preventative treatment is offered to all LTBI positive individuals, then progression to active TB may be prevented, but the number needed to treat is >20 indicating many unnecessary treatments
Solution Approach 1:
The patent performs preliminary risk assessment using detailed immune profiling before committing to preventative treatment. By measuring multiple immune parameters (T-cell subsets, activation markers, cytokine profiles) upfront, the system identifies individuals at highest risk of progression, enabling targeted treatment strategies that avoid unnecessary treatment of low-risk individuals.
Solution Approach 2:
The patent establishes feedback loops through longitudinal monitoring of immune parameters to dynamically adjust treatment decisions. By tracking changes in T-cell activation markers and cytokine production over time, the system provides feedback on progression risk, allowing clinicians to intensify or discontinue treatment based on actual risk rather than static initial test results.
3Measurement precision
If multiple invasive tests such as CT with contrast, bronchoscopy, biopsy or PET scanning are used to investigate TB, then diagnostic accuracy may be improved, but the procedures are time consuming and expensive
Solution Approach 1:
The patent replaces mechanical/invasive diagnostic procedures (bronchoscopy, biopsy, PET scanning) with an in vitro immune-based assay system. By culturing patient T-cells and measuring their immune responses to mycobacterial antigens in the laboratory, the system achieves high diagnostic accuracy without subjecting patients to invasive procedures, reducing both time loss and procedural risks.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The test effectively stratifies individuals with latent TB infection based on their risk of progressing to active TB, allowing for more targeted and effective preventative treatment, thereby reducing the number of people needed to treat to prevent one case of active TB.
Implementation Method 1
identifying T-cells in the sample that are CD4 positive and secrete IFN-γ in response to TB antigens
Implementation Method 2
identifying those cells of (iii) which are also HLA-DR positive
Data Source
AI summary
There are provided methods of method of determining the latent tuberculosis (TB) infection status in an individual comprising: (i) providing a sample comprising T-cells; (ii) exposing the sample of (i) to one or more TB antigens; (iii) identifying T-cells in the sample that are CD4 positive and secrete IFN-γ in response to TB antigens; (iv) identifying those cells of (iii) which are also HLA-DR positive; and optionally (v) calculating the cells identified in (iv) as a percentage of those identified in (iii); wherein the identification of cells in (iv) and/or the percentage of cells calculated in (v) correlates to latent TB infection status of the individual, and wherein steps (iii) and (iv) can be carried out either sequentially or simultaneously. There are also provided compositions and kits for use in such methods.