FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells.
Following the present concepts, the synthetic sphingosine analog of myriocin FTY720 alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. However, several studies indicate that the immunosuppressive properties of FTY720 may alternatively be due to tolerogenic activities via modulation of dendritic cell differentiation or based on direct effects on CD4(+)CD25(+) regulatory T cells (Treg). As Treg play an important role for the cure of inflammatory colitis, we used the Th1-mediated 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model to address the therapeutic potential of FTY720 in vivo. A rectal enema of TNBS was given to BALB/c mice. FTY720 was administered i.p. from days 0 to 3 or 3 to 5. FTY720 substantially reduced all clinical, histopathologic, macroscopic, and microscopic parameters of colitis analyzed. The therapeutic effects of FTY720 were associated with a down-regulation of IL-12p70 and subsequent Th1 cytokines. Importantly, FTY720 treatment resulted in a prominent up-regulation of FoxP3, IL-10, TGFbeta, and CTLA4. Supporting the hypothesis that FTY720 directly affects functional activity of CD4(+)CD25(+) Treg, we measured a significant increase of CD25 and FoxP3 expression in isolated lamina propria CD4(+) T cells of FTY720-treated mice. The impact of FTY720 on Treg induction was further confirmed by concomitant in vivo blockade of CTLA4 or IL-10R which significantly abrogated its therapeutic activity. In conclusion, our data provide clear evidence that in addition to its well-established effects on migration FTY720 leads to a specific down-regulation of proinflammatory signals while simultaneously inducing functional activity of CD4(+)CD25(+) Treg. Thus, FTY720 may offer a promising new therapeutic strategy for the treatment of IBD.
Daniel
Carolin
C
First Department of Internal Medicine, Entwicklung und Sicherheit-ZAFES, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Sartory
Nico
N
Zahn
Nadine
N
Geisslinger
Gerd
G
Radeke
Heinfried H
HH
Stein
Juergen M
JM
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D001388:Aziridines / Q000633:toxicity; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000187:drug effects; D002794:Choline / Q000031:analogs & derivatives / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D051858:Forkhead Transcription Factors / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009466:Neuromuscular Blocking Agents / Q000633:toxicity; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001388:Aziridines; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D009466:Neuromuscular Blocking Agents; D011409:Propylene Glycols; C044894:ethylcholine aziridinium; D000068876:Fingolimod Hydrochloride; D002794:Choline; D013110:Sphingosine