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

TY - JOUR

T1 - Reconstitution of Scid mice with CD4+CD25- T cells leads to rapid colitis: an improved model for pharmacologic testing

AU - Kjellev, Stine

AU - Lundsgaard, Dorthe

AU - Poulsen, Steen Seier

AU - Markholst, Helle

PY - 2006/8/1

Y1 - 2006/8/1

N2 - 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 approximately 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-1beta 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.

AB - 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 approximately 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-1beta 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.

KW - Adoptive Transfer

KW - Animals

KW - Antigens, CD11c

KW - Antigens, CD4

KW - CD4-Positive T-Lymphocytes

KW - Colitis

KW - Colon

KW - Cytokines

KW - Disease Models, Animal

KW - Epithelium

KW - Female

KW - Goblet Cells

KW - Immunohistochemistry

KW - In Situ Hybridization

KW - Inflammation

KW - Inflammation Mediators

KW - Intestinal Mucosa

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, SCID

KW - Occult Blood

KW - Peptides

KW - Receptors, Interleukin-2

U2 - 10.1016/j.intimp.2006.04.017

DO - 10.1016/j.intimp.2006.04.017

M3 - Journal article

C2 - 16782548

SN - 1567-5769

VL - 6

SP - 1341

EP - 1354

JO - International Immunopharmacology

JF - International Immunopharmacology

IS - 8

ER -