Therapeutic benefit of pentostatin in severe IL‐10−/− Colitis

• Published in: Inflammatory bowel diseases 2008-07, Vol.14 (7), p.880-887
• Main Authors: Brown, Jeffrey B., Lee, Goo, Grimm, Gery R., Barrett, Terrence A.
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine deaminase; Adenosine Deaminase Inhibitors; Amyloid; animal models of IBD; Animals; Antimetabolites; CD4 antigen; CD4-Positive T-Lymphocytes - physiology; Cell activation; Cells, Cultured; Colitis; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colon; CXCL10 protein; Cytokines; Cytokines - biosynthesis; Effector cells; Enzyme Inhibitors - therapeutic use; Enzyme-Linked Immunosorbent Assay; Foxp3 protein; IL‐10‐/‐ colitis; Imidazoles; inflammation; Inflammatory bowel diseases; Interferon; Interleukin 1; Interleukin 6; Interleukin-10 - deficiency; Intestine; Leukemia; Lymph nodes; Lymphocyte Depletion; Lymphocyte Subsets - cytology; Lymphocytes T; Mice; Mice, Inbred C57BL; Mucosa; pentostatin; Pentostatin - therapeutic use; pharmacotherapy; piroxicam; Polymerase Chain Reaction; purines; regulatory T cells; Tumor necrosis factor
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1002/ibd.20410

Background: Pentostatin, an adenosine deaminase (ADA) inhibitor, is a purine antimetabolite used for the treatment of leukemias. ADA inhibition blunts expansion of proliferating lymphocytes and increases adenosine release, a potent anti‐inflammatory molecule. Human inflammatory bowel disease (IBD) is driven by expansion of effector T cells (Teff) that overwhelm reulatory T cells (Treg) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair Teff cell expansion and reduce inflammatory cytokine release in IL‐10‐deficient (IL‐10‐/‐) mice. Methods: Colitis was induced in IL‐10‐/‐ mice by administering piroxicam for two weeks. Mice were treated with daily pentostatin or phosphate‐buffered saline for 1 week and effects on tissue inflammation, lymphocyte numbers and cytokine production examined. Results: Pentostatin reduced inflammation by >50% and nearly normalized serum amyloid A levels. Lymphocyte expansions in the colon and mesenteric lymph node (MLN) (3.5‐fold and >5‐fold respectively) dropped by >50‐90%. Pro‐inflammatory factors in the colon and MLN (IL‐1β, IFN‐γ, IL‐6, CXCL10, TNF) dropped whereas FoxP3 and TGF‐β were unchanged. Reductions in cytokine production from equivalent numbers of T cells from pentostatin‐treated mice after in vitro (36h) or in vivo (3h) activation suggested anti‐inflammatory effects of pentostatin independent of lymphodepletion contributed to its therapeutic benefit. Analysis of mucosal lymphocyte subsets suggested pentostatin reduced numbers of effector CD4+ CD69+ T cells, while sparing CD4+ CD62L+ T cells. Conclusions: Pentostatin dosages that avoid severe lymphocyte depletion effectively treat colitis by impairing Teff cell expansion and reducing pro‐inflammatory cytokine production while preserving regulatory Treg populations and function. (Inflamm Bowel Dis 2008)