Overview of models, methods, and reagents developed for translational autoimmunity research in the common marmoset (Callithrix jacchus)

Abstract

The common marmoset (Callithrix jacchus) is a small-bodied Neotropical primate and a useful preclinical animal model for translational research into autoimmune-mediated inflammatory diseases (AIMID), such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The animal model for MS established in marmosets has proven their value for exploratory research into (etio) pathogenic mechanisms and for the evaluation of new therapies that cannot be tested in lower species because of their specificity for humans. Effective usage of the marmoset in preclinical immunological research has been hampered by the limited availability of blood for immunological studies and of reagents for profiling of cellular and humoral immune reactions. In this paper, we give a concise overview of the procedures and reagents that were developed over the years in our laboratory in marmoset models of the above-mentioned diseases.

Fig. 1.

Magnetic resonance imaging (MRI) sequences of marmoset EAE brain. A. MRI images were collected in vivo for animal M06061 at the time of clinically evident EAE symptoms. In each figure, the same slice position is shown. See also Table 7 for an explanation of the several MRI techniques. Arrowheads in the T2W image point to white matter lesions. Unique tor in vivo MRI is the possibility to measure the integrity of the blood brain barrier with intravenously injected gadolinium-based contrast agent. The depicted T1W Gd leakage image displays the increase in MRI signal intensity as a result of contrast leakage. B. The brain of the same monkey (M06061) with EAE symptoms was used for a postmortem MRI analysis. As with postmortem material, a higher signal intensity results in an increase in lesion detail. Arrowheads in the T2W image point to lesions in the white matter. Suppression of the signal intensity of the white matter, i.e., WAIR imaging, improves the detection of cortical grey matter pathology. Lesions in the cortex are indicated by arrow heads in the WAIR image. C. Three animals with increasing levels of MRI abnormalities in the brain are shown with almost identical EAE scores (left brain=M07076 EAE score 2.25; middle brain=Mi12699 EAE score 2.25; right brain=M07079 EAE score 2.5). 3D data sets are generated from postmortem MR images. Lesions in the white matter were determined on T2W images, and lesions in the cortex were determined on WAIR images.

Fig. 2.

Histology and immunohistochemistry of the spinal cord, optic nerve, and brain of monkey M06061, which was sacrificed with EAE symptoms. The MRI data from this monkey are depicted in Fig. 1. Staining with Kluver-Barrera (KLB) shows the intense demyelination in the spinal cord (A), optic nerve (B), and brain (C) (bars 500 µm). The positioning of the depicted brain white matter lesion (C) in the corpus callosum is indicated by the rectangle in the insert. The arrowhead in C points at a blood vessel that is further magnified in F and I. CD3 staining shows the presence of inflammation in the spinal cord (D), optic nerve (E), and brain (F) (bars 50 µm). The spinal cord was also stained with anti-PLP (G, bar 100 µm), and the optic nerve was stained for macrophages with MRP14 (H, bar 100 µm). The insert in H shows PLP degradation products in macrophages. The corpus callosum stained with MRP14 for phagocytic macrophages (I, bar 100 µm). Cortical demyelination was verified by PLP staining (J, bar 200 µm), and the activated macrophages/microglia at the border of demyelination were visualized by staining with MRP14 (K, 200 µm). Staining for CD3 shows the presence of a large amount of T cells in the meninges and at the active border of demyelination (L, 200 µm).