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Development of antigen induced colitis in SCID mice reconstituted with spleen derived memory type CD4⁺ CD45RB⁺ T cells

¹ Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan
² Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan and Department of Clinical Pathology, Nihon University, School of Dentistry at Matsudo, Chiba 271, Japan
³ Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan and Pharmaceutical Division, Pola Chemical Industries, INC, Yokohama 244, Japan
⁴ Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan and Immunobiology Vaccine Centre, Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

Correspondence to:
Correspondence to:
Dr H Kiyono, Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565, Japan;
kiyono{at}biken.osaka-u.ac.jp

ABSTRACT
Background and aims: Enteric bacterial and/or food antigens may be crucial in the development of colitis but little is known of the exact mechanism of antigen specific reactions in this condition. The aim of this study was to determine whether systemically primed antigen specific CD4⁺ T cells containing both CD45RB^high and CD45RB^low populations participate as a pathogenic subset that in turn leads to inflammatory reactions selectively in the large intestine.

Methods: SCID mice were reconstituted with splenic CD4⁺ CD45RB⁺ T cells or CD4⁺ CD45RB^low T cells isolated from donor mice systemically primed with ovalbumin (OVA) plus CFA. The reconstituted mice were then fed OVA for several weeks.

Results: Reconstitution of SCID mice with OVA primed splenic CD4⁺ T cells, containing populations of CD45RB^high and CD45RB^low, resulted in the development of colitis by 4–5 weeks following repeated administration of oral OVA. Histopathological study revealed thickened wall, inflammatory cell infiltration, crypt elongation, and loss of goblet cells in the large intestine. The CD4⁺ CD45RB^low population of cells extracted from the affected large intestine secreted high levels of interferon (IFN-) and tumour necrosis factor (TNF-) at the protein and mRNA levels. Administration of neutralising antibodies to TNF-, but not to IFN-, prevented the development of colitis. Furthermore, adoptive transfer with OVA primed splenic CD4⁺ CD45RB^low T cells evoked severe colitis.

Conclusions: These results demonstrate that systemically primed activated/memory CD4⁺ CD45RB^low T cells can mediate the development of specific antigen induced colitis in SCID mice, and also that TNF- is critical in the induction of this type of colitis. Our results contrast with those from studies in some colitis models in which CD45RB^low T cells appeared to prevent colitis through secretion of immunosuppressive cytokines.

Keywords: SCID; colitis; T cells; ovalbumin; tumour necrosis factor

Abbreviations: TNF-, tumour necrosis factor ; IFN-, interferon ; OVA, ovalbumin; TCR, T cell receptor; PBS, phosphate buffered saline; mAb, monoclonal antibody; IL, interleukin; RT-PCR, reverse transcription-polymerase chain reaction; ICAM-1, intercellular adhesion molecule 1; TGF-ß, transforming growth factor ß; CFA, complete Freund adjuvant; LFA, lymphocyte function associated antigen; KLH, keyhole limpet haemocyanin

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