Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV

Tanaka, Sumiko; Murakami, Takanori; Horikawa, Hiroshi; Sugiura, Masaki; Kawashima, Keisuke; Sugita, Takahisa

doi:10.1016/s0192-0561(97)00004-0

Cited by 90 publications

(49 citation statements)

References 41 publications

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“…Other inhibitors of CD26/DPP-IV have previously been reported to suppress immune responses in allograft rejection (48), experimental arthritis (49), and autoimmune encephalomyelitis (50). In contrast to these observations, the present studies demonstrate that PT-100 can stimulate T-cell immunity and, in the EL4 model, elicit CTL priming.…”

Section: Antitumor Effect Of Dpp Inhibitor Pt-100contrasting

confidence: 94%

PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

Adams¹,

Miller²,

Jesson³

et al. 2004

Cancer Research

182

162

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The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20 ؉ B-cell lymphoma and HER-2 ؉ colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/ DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26 Ϫ/Ϫ mice.

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Section: Antitumor Effect Of Dpp Inhibitor Pt-100contrasting

confidence: 94%

PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

Adams¹,

Miller²,

Jesson³

et al. 2004

Cancer Research

182

162

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“…This association with early stage disease may suggest pro-fibrogenic roles of DPP8 and DPP9. Though DPPs have been implicated in inflammation and inflammatory diseases [28,29,54] , no change in DPP expression was observed in hepatic lymphocytes in this early stage fibrosis, suggesting that hepatocytes, which constitute more than 80% of the liver cell population, are probably the major source of upregulated DPP8 and DPP9 in this liver fibrosis model.…”

mentioning

confidence: 70%

“…An inhibitor selective for DPP8 and DPP9 vs related proteases can suppress DNA synthesis in mitogenstimulated splenocytes from both wildtype DPP4 + / + and DPP4 -/ -gene knockout (gko) mice [27] . Moreover, DPP8 and DPP9 have been implicated in hematopoiesis and in inflammatory diseases including arthritis [2,28,29] . Most importantly, DPP8 and DPP9 are involved in processing and degradation of peptides involved in antigen presentation by Major histocompatibility complex class I [30] .…”

Section: Introductionmentioning

confidence: 99%

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Chowdhury

Chen²,

Yao³

et al. 2013

WJG

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), human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen (PWM) or lipopolysaccharide (LPS), and in dithiothreitol (DTT) and mitomycin-C treated Raji cells. DPP8 and DPP9 expression were measured in epidermal growth factor (EGF) treated Huh7 hepatoma cells, in fibrotic liver samples from mice treated with carbon tetrachloride (CCl4) and from multidrug resistance gene 2 (Mdr2 /Abcb4 ) gene knockout (gko) mice with biliary fibrosis, and in human end stage primary biliary cirrhosis (PBC). RESULTS:All three lymphocyte subsets expressed DPP8 and DPP9 mRNA. DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T-and Raji B-cell lines. DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells. DPP9-transfected Raji cells exhibited more annexin V + cells and associated apoptosis. DPP8 and DPP9 mRNA were upregulated in CCl4 induced fibrotic livers but not in the lymphocytes isolated from such livers, while DPP9 was upregulated in EGF stimulated Huh7 cells. In contrast, intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers. CONCLUSION:These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.

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“…DPP-4 activity is significantly higher in OA synovial fluid compared with RA synovial fluid (117), whereas synovial membrane activity has been reported to be either similar in patients with RA and those with OA (118) or higher in patients with RA (119). In RA animal models (adjuvant-induced arthritis, alkyldiamine-induced arthritis, or CIA), DPP-4 inhibition suppressed arthritis development (120,121), although the severity of antigeninduced arthritis increased in DPP-4 Ϫ/Ϫ mice (122).…”

Section: Dppsmentioning

confidence: 99%