Therapeutic benefit of pentostatin in severe IL-10-/- colitis

Abstract

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. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.