Therapeutic benefit of pentostatin in severe IL-10-/- colitis.
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 (T(eff)) that overwhelm reulatory T cells (T(reg)) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair T(eff) 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-1beta, IFN-gamma, IL-6, CXCL10, TNF) dropped whereas FoxP3 and TGF-beta 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 T(eff) cell expansion and reducing pro-inflammatory cytokine production while preserving regulatory T(reg) populations and function.
Brown
Jeffrey B
JB
Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Lee
Goo
G
Grimm
Gery R
GR
Barrett
Terrence A
TA
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles; D016753:Interleukin-10 / Q000172:deficiency*; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D015649:Pentostatin / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction
D058892:Adenosine Deaminase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016753:Interleukin-10; C039686:piroximone; D015649:Pentostatin