Reconstitution of Scid mice with CD4 +CD25 − T cells leads to rapid colitis: An improved model for pharmacologic testing

• Published in: International immunopharmacology 2006-08, Vol.6 (8), p.1341-1354
• Main Authors: Kjellev, Stine, Lundsgaard, Dorthe, Poulsen, Steen Seier, Markholst, Helle
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Adoptive Transfer - adverse effects; Adoptive Transfer - methods; Animals; Biological and medical sciences; CD11c Antigen - analysis; CD4 + T lymphocytes; CD4 Antigens - analysis; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; Colitis; Colitis - etiology; Colitis - immunology; Colitis - pathology; Colon - metabolism; Colon - pathology; Cytokines; Cytokines - blood; Disease Models, Animal; Epithelial proliferation; Epithelium - immunology; Epithelium - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Goblet Cells - metabolism; Immunohistochemistry; In Situ Hybridization; Inflammation - etiology; Inflammation - immunology; Inflammation - pathology; Inflammation Mediators - metabolism; Inflammatory bowel disease; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, SCID; Occult Blood; Other diseases. Semiology; Peptides - genetics; Peptides - metabolism; Pharmacology. Drug treatments; Receptors, Interleukin-2 - analysis; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Trefoil Factor-2
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2006.04.017

Improved experimental colitis models are needed for evaluation of treatment strategies for IBD. Most current models either lack resemblance to IBD, are complicated to establish, or the colitis occurs slowly and inconsistently. Our aim was to characterize the course of colitis in C.B-17 Scid mice reconstituted with syngeneic CD25-depleted CD4 + cells, including the identification of useful biomarkers, and assessment of the similarities to IBD with focus on the relationship between colonic epithelial proliferation and inflammatory parameters. Groups of reconstituted and un-reconstituted mice were sacrificed weekly from week 1 to 4. Clinical signs of colitis occurred ∼ 2 weeks after reconstitution. Disease onset and severity based on histopathology correlated well with the colonic weight:length ratio, fecal consistency score, presence of occult blood in feces, and fecal IL-1β content. Loss in body weight was not apparent until colitis was well established and exhibited lower coefficient of correlation to the histologic score. Early colonic histopathology was dominated by epithelial hyperproliferation, loss of mucus and mild lymphoid infiltration. Epithelial hyperproliferation was paralleled by increased fecal soluble tumor necrosis factor receptor II content. Cytokines in colonic tissue homogenates exhibited a Th1-like profile. We conclude that adoptive transfer of CD4 +CD25 − T cells results in colitis resembling IBD with a rapid onset and limited variability between individuals. Purification of CD4 +CD25 − T cells is a simple procedure, and does not require flow-cytometric sorting. Fecal consistency score and colonic weight:length ratio are readily measurable and consistent disease parameters. This model is thus highly suitable for pharmacological testing of intervention strategies.