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ORIGINAL RESEARCH ARTICLE

Sudden Onset of Colitis After Ablation of Secretin-Expressing Lymphocytes in Transgenic Mice

Guido Rindi^*,1, Monica Civallero^,, Maria Elena Candusso, Annalisa Marchetti^||, Catherine Klersy^||, Rosanna Nano and Andrew B. Leiter^¶

^* Department of Pathology, University of Parma, Italy; Department of Animal Sciences, University of Pavia, Italy; Department of Medical, Oncological and Radiological Sciences, University of Modena, Italy; Department of Pathology, University of Pavia, Italy; ^|| Scientific Direction, IRCCS Policlinico San Matteo, Pavia, Italy; and ^¶ New England Medical Center, Division of Gastroenterology, GRASP Digestive Disease Center and Tupper Research Institute, Boston, Massachusetts 02111

To whom requests for reprints should be addressed at ¹ Dipartimento di Patologia e Medicina di Laboratorio, Sezione di Anatomia Patologica, Università di Parma, Via Gramsci, 14 I-43100 Parma, Italy. E-mail: guido.rindi{at}unipr.it

Though secretin mRNA was demonstrated in mouse lymphoid organs, its role in the immune system is unknown. Here, secretin gene-expressing cells were ablated by ganciclovir infusion in mice transgenic for the rat secretin promoter (Sec) directing the expression of herpesvirus thymidine kinase (Sec-HSVTK). Thymus, spleen, blood, and colon were investigated by histology. Lymphoid cells were extracted and quantified, and CD19⁺ B-cells and CD3⁺, CD103⁺, CD4⁺, and CD8⁺ T-cells were analyzed by flow cytometry. Protein extracts from spleen and thymus were assayed for secretin by Western blotting, and isolated lymphocytes were investigated for HSVTK, secretin, and secretin receptor (Sec-R) mRNA by reverse transcription–polymerase chain reaction (RT-PCR). Ablation of secretin-expressing cells produced severe colitis with morphological features similar to those observed in graft-versus-host (GVH) disease. Profound lymphoid depletion was observed in spleen, thymus, and peripheral blood. The relative percentage of B- and T-cell subsets were unaffected. Analysis of colonic lymphocytes revealed a marked depletion of CD4⁺ T lymphocytes. Colitis and lymphoid depletion were not reversed by secretin cotreatment. Immunoblot analysis of protein extracts from spleen and thymus identified secretin-like immmunoreactant. RT-PCR of lymphocyte mRNA from spleen and thymus identified secretin and secretin receptor transcripts. We conclude that GVH-like colitis in ganciclovir-treated Sec-HSVTK mice arises from depletion of secretin gene–expressing lymphoid cells and not from the failure of secretin production.

Key Words: secretin • ablation • thymus • spleen • Sec-HSVTK • colitis • cytometry

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