Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin {alpha}4{beta}1-Expressing Immune Cells [NOVEL IMMUNOLOGICAL METHODS]

Positron emission tomography and computed tomography imaging (PET/CT) is an increasingly valuable tool for diagnosing tuberculosis (TB). The glucose analog [¹⁸F]fluoro-2-deoxy-2-d-glucose ([¹⁸F]-FDG) is commonly used in PET/CT that is retained by metabolically active inflammatory cells in granulomas, but lacks specificity for particular cell types. A PET probe that could identify recruitment and differentiation of different cell populations in granulomas would be a useful research tool and could improve TB diagnosis and treatment. We used the Mycobacterium-antigen murine inflammation model and macaques with TB to identify [⁶⁴Cu]-labeled CB-TE1A1P-PEG₄-LLP2A ([⁶⁴Cu]-LLP2A), a high affinity peptidomimetic ligand for very late Ag-4 (VLA-4; also called integrin α4β1) binding cells in granulomas, and compared [⁶⁴Cu]-LLP2A with [¹⁸F]-FDG over the course of infection. We found that [⁶⁴Cu]-LLP2A retention was driven by macrophages and T cells, with less contribution from neutrophils and B cells. In macaques, granulomas had higher [⁶⁴Cu]-LLP2A uptake than uninfected tissues, and immunohistochemical analysis of granulomas with known [⁶⁴Cu]-LLP2A uptake identified significant correlations between LLP2A signal and macrophage and T cell numbers. The same cells coexpressed integrin α4 and β1, further supporting that macrophages and T cells drive [⁶⁴Cu]-LLP2A avidity in granulomas. Over the course of infection, granulomas and thoracic lymph nodes experienced dynamic changes in affinity for both probes, suggesting metabolic changes and cell differentiation or recruitment occurs throughout granuloma development. These results indicate [⁶⁴Cu]-LLP2A is a PET probe for VLA-4, which when used in conjunction with [¹⁸F]-FDG, may be a useful tool for understanding granuloma biology in TB.

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