FTY720, an immunosuppressant, attenuates chronic pancreatitis in rats by suppressing T-cell infiltration.
OBJECTIVE
FTY720, a novel synthetic immunosuppressant, decreases peripheral blood lymphocytes by accelerating their homing to the peripheral and mesenteric lymph nodes and Peyer's patches. We previously reported that tacrolimus, another immunosuppressant, attenuates chronic pancreatitis by suppressing T-cell infiltration in male Wistar Bonn/Kobori rats but also may cause toxicity. To assess the effects of FTY720 on the development of pancreatic inflammation and fibrosis in the same model, the agent dissolved in physiologic saline was subcutaneously injected to 10-week-old male WBN/Kob rats for 10 weeks.


METHODS
Parameters for inflammation and fibrosis were assessed and interferon-gamma and transforming growth factor-beta1 mRNA in the pancreas were determined by RT-PCR.


RESULTS
Treatment with FTY720 attenuated gross alterations in the pancreas, including pigmentation and atrophy. This protective effect was quantitatively confirmed by significant increase in pancreatic weights and decreases in pancreatic myeloperoxidase activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. The obvious infiltration of CD4- and CD8-positive T cells into the pancreas in the saline group was almost completely prevented by administration of FTY720, which also suppressed overexpression of interferon and transforming growth factor-beta1 mRNA in the pancreas.


CONCLUSIONS
We conclude that FTY720 prevents pancreatic inflammation and fibrosis by suppressing infiltration of CD4- and CD8-positive T cells and by downregulating induction of interferon and transforming growth factor-beta1 mRNA in the pancreas.
Okamoto
Tetsu
T
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Yamada
Tamaki
T
Kuno
Atsushi
A
Ogawa
Kumiko
K
Tang
Mingxi
M
Sano
Hitoshi
H
Ohara
Hirotaka
H
Nakao
Haruhisa
H
Kataoka
Hiromi
H
Shirai
Tomoyuki
T
Itoh
Makoto
M
D000818:Animals; D001835:Body Weight; D000068876:Fingolimod Hydrochloride; D006909:Hydroxyproline / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics; D008297:Male; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D050500:Pancreatitis, Chronic / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D009195:Peroxidase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D006909:Hydroxyproline