Quantitative tomography of early-onset spontaneous AA amyloidosis in interleukin 6 transgenic mice.
Mice that constitutively express the human interleukin 6 (huIL6) protein from a heritable transgene (H2-L(d)-IL-6) express high levels of the acute-phase reactant, serum amyloid protein A, a liver-derived apoprotein of high-density lipoprotein that is the precursor of AA amyloid. Typically at approximately 5 mo of age B6(C)- Tg(H2-L(d)-IL-6)Kish (H2/huIL-6) animals begin to develop splenic deposits of AA amyloid, which progress to involve the liver, kidney, and vasculature, ultimately resulting in death due to severe systemic AA amyloidosis at 8 to 9 mo of age. These mice provide a robust model in which to study novel therapeutic and diagnostic imaging agents for AA amyloidosis. We recently have noted a change in onset of spontaneous disease, as evidenced by 2 female transgenic mice that were found moribund at only 5 mo of age. Extensive hepatosplenic amyloid deposits in both mice were identified and quantified by single-photon emission computed tomography, which further revealed heterogeneous distribution of radiotracer in the spleen indicating a distinction between amyloid-laden red pulp and the disease-free lymphoid follicles. The AA nature of the deposits was evidenced immunohistochemically and by mass spectrometric analyses of extracted amyloid fibrils. Our studies have documented the manifestation of early-onset, severe, spontaneous AA amyloidosis in 2- to 5-mo-old H2/ huIL-6 mice; we hypothesize that this disease is due to genetic rather than environmental factors.
Wall
Jonathan S
JS
Human Immunology and Cancer Program, Graduate School of Medicine, University of Tennessee, Knoxville, TN, USA. jwall@mc.utmck.edu
Richey
Tina
T
Allen
Amy
A
Donnell
Robert
R
Kennel
Steve J
SJ
Solomon
Alan
A
D000367:Age Factors; D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
C508600:IL6 protein, human; D015850:Interleukin-6; D010446:Peptide Fragments; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein