Immunology studies in non-human primate models of tuberculosis

Abstract

Non-human primates, primarily macaques, have been used to study tuberculosis for decades. However, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in Mycobacterium tuberculosis infection. Low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. Reagents from humans are usually cross-reactive with macaques, further facilitating the use of this model system to study tuberculosis. Finally, macaques develop the spectrum of granuloma types seen in humans, providing a unique opportunity to investigate bacterial and host factors at the local (lung and lymph node) level. Here, we review the past decade of immunology and pathology studies in macaque models of tuberculosis.

Keywords: granuloma; immunology; lymph node; macaque; non-human primate; tuberculosis.

Fig. 1. NHP granulomas exhibit the organizational characteristics of human granulomas

(A). Hematoxylin and eosin stained section of lung tissue containing a necrotic granuloma with a large central region of caseous necrosis (10× magnification). (B). Immunohistochemical staining of a necrotic granuloma showing CD68⁺ macrophages (green) surrounding the necrotic center (unstained) and CD3⁺ T cells (red) in the lymphocyte cuff. Scattered clusters of alveolar macrophages, characterized by their morphology and strong CD68 expression, can be seen at the edge of the granuloma and in the adjacent lung tissue. Nuclei are stained in blue (20× magnification).

Fig. 2. Diagrammatic representation of the macaque tracheobronchial tree depicting draining mediastinal lymph nodes observed in NHPs following Mtb infection

Cranial hilar lymph nodes and the carinal lymph nodes on the right and left side of the airways are most commonly observed. (Abbreviations: LN, lymph node; L, left; R, right).

Fig. 3. Three dimensional ¹⁸F-FDG PET/CT image showing lymph nodes and granulomas in a macaque three weeks post Mtb infection

Increased uptake of FDG is observed in cranial hilar and carinal lymph nodes (yellow arrows). Small lung granulomas (blue arrows) with variable FDG uptake are also observed as early as 3 weeks post infection.

Fig. 4. Axial section of ¹⁸F-FDG PET/CT image showing macaque lung granulomas

In NHPs, various types and numbers of lung granulomas are observed with variable FDG uptake within a lobe in both active disease and latent infection. Arrows indicate both metabolic active-PET hot (yellow) and PET cold (blue) granulomas seen within a lobe.