Novel immunosuppressive effect of FK506 by augmentation of T cell apoptosis

Abstract

SUMMARYWe have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. In this study, we examined the effects of FK506 in this mouse model in preventing autoimmune pancreatitis and investigated its action on calcium signalling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treated with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mononuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltration associated with destruction of acini and partial fatty changes were observed in 25-week-old control mice. In contrast, FK506 treated mice showed almost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-treated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using naive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppressive effect of FK506 on Bcl-2 production but not on Bax production was confirmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its beneficial effect on aly autoimmune pancreatitis.

A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis

“…In addition, cases without systemic autoimmune diseases have been reported, which has led to the concept of an autoimmune related pancreatitis [2,3], so called "autoimmune pancreatitis" (AIP), proposed by Yoshida [2]. These findings support the hypothesis that an autoimmune mechanism may be involved in the pathogenesis and pathophysiology in a proportion of patients with pancreatitis [17][18][19][20][21], possibly mediated by an overactive apoptosis [7][8][9][10]22].…”

“…Occasionally, the granulocytic infiltration extends into the small intralobular ducts and acini [50]. These findings suggest that leukocyte recruitment and activation of the oxidative burst [55] may contribute to the pathophysiology of AIP; (e) T cells are involved in inducing apoptosis of acinar cells [7,56]. In particular, CD4 T cells exert direct cytotoxic effects through Fas ligand (FasL) expression [3], and FasL, TNF-α and TUNEL(+) apoptotic cells have been detected among pancreas-infiltrating cells [9].…”

“…These major lymphocytic infiltrations may contribute to tissue destruction probably by apoptosis [7][8][9][10]. In approximately 60%, the coexistence of this type of pancreatitis with other autoimmune diseases such as Sjögren's syndrome (SjS), sclerosing extrahepatic cholangitis [interpreted as a variant of primary sclerosing cholangitis (PSC) or as an inflammatory pseudotumor], primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), or other extrapancreatic disorders, such as retroperitoneal fibrosis, salivary gland swelling, inflammatory bowel disease (IBD), Hashimoto's thyroiditis, and recently gastric peptic ulceration has been reported [4][5][6]11].…”

A Double-blind Randomized Trial of 0.1% Tacrolimus vs 0.05% Clobetasol for the Treatment of Childhood Vitiligo

“…12 tosis in vitro and down-regulates IL-8 keratinocyte surface receptors. 14 Systemic tacrolimus has been used in a number of applications, particularly to avoid graft rejection. 15 Topical tacrolimus is a safe and effective treatment for inflammatory skin diseases, particularly atopic dermatitis, psoriasis, pyoderma gangrenosum, alopecia areata, and other illnesses with immunologic disarrangement.…”

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

“…Frequently, more than one mechanism is involved in drug-induced immunosuppression, and apoptosis has recently been recognized as one of these mechanisms. Immunosuppressive tautomycetin and FK506 were reported to induce apoptosis of lymphocytes as well as inhibit TCR-induced signaling and IL-2R-mediated signaling, respectively (12,13). Several metabolic inhibitors, including methotrexate and mycophenolic acid of mycophenolate mofetil, also elicited apoptosis of lymphocytes (14,15) and methotrexate-induced apoptosis of activated human PBL occurred independently from Fas/Fas ligand (FasL) interaction.…”