Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225

Tanaka, Sumiko; Murakami, Takanori; Nonaka, Nobuaki; Ohnuki, Takashi; Yamada, Masaki; Sugita, Takahisa

doi:10.1016/s0162-3109(98)00014-9

Cited by 48 publications

(31 citation statements)

References 15 publications

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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%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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Section: Dppsmentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…14 -16 These studies in RA patients, and similar ones in experimental mouse models of RA 17 suggested that decreased levels of CD26 are associated with severity of inflammation in RA. Paradoxically, it has been reported that pharmacological inhibition of DPPIV enzyme activity could reduce the progression of arthritis in an experimental rat model of RA, 18,19 suggesting that decreases in DPPIVactivity may alleviate inflammation under some circumstances, and based on these results it was proposed that DPPIV-inhibitors may be useful as treatment of RA. 20 However, these inhibitors may have inhibited not just CD26, but also other enzymes that exhibit similar enzyme activity.…”

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confidence: 99%

Circulating CD26 Is Negatively Associated with Inflammation in Human and Experimental Arthritis

Busso

Wagtmann

Herling

et al. 2005

The American Journal of Pathology

182

151

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Dipeptidyl peptidase IV (DPPIV, CD26), a proteasecleaving N-terminal X-Pro dipeptide from selected proteins including some chemokines, is expressed both as a soluble form in plasma and on the cell surface of various immune and nonimmune cell types. To gain insights into the pathophysiological role of CD26 in arthritis, we explored DPPIV/CD26 expression during murine antigen-induced arthritis (AIA), an experimental model of arthritis. AIA induction led to reduced plasma DPPIV activity. In CD26-deficient mice, the severity of AIA was increased as assessed by enhanced technetium uptake and by increased histological parameters of inflammation (synovial thickness and exudate). We demonstrated that CD26 controls the in vivo half-life of the intact active form of the proinflammatory chemokine stromal cellderived factor-1 (SDF-1). CD26-deficient mice exhibited increased levels of circulating active SDF-1, associated with increased numbers of SDF-1 receptor (CXCR4)-positive cells infiltrating arthritic joints. In a clinical study, plasma levels of DPPIV/CD26 from rheumatoid arthritis patients were significantly decreased when compared to those from osteoarthritis patients and inversely correlate with C-reactive protein levels. In conclusion, decreased circulating CD26 levels in arthritis may influence CD26-mediated regulation of the chemotactic SDF-1/CXCR4 axis.

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“…The CD26 molecule functions as the cell membrane-associated exopeptidase dipeptidyl peptidase (DP) 4 IV (EC 3.4.14.5), an enzyme capable of cleaving N-terminal dipeptides from polypeptides with either proline or alanine residues at the penultimate position (1)(2)(3). Many recent reports have demonstrated that CD26/DP IV serves as an important regulator of immune responses by affecting T cell activation, proliferation, and cytokine production (1)(2)(3)(4)(5)(6)(7)(8). Subsequently, multiple roles were predicted for CD26/DP IV in leukocyte homing and inflammation.…”

mentioning

confidence: 99%

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

Preller

Gerber

Wrenger

et al. 2007

The Journal of Immunology

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The T cell marker CD26/dipeptidyl peptidase (DP) IV is associated with an effector phenotype and markedly elevated in the human CNS disorder multiple sclerosis. However, little is known about the in vivo role of CD26/DP IV in health and disease, and the underlying mechanism of its function in CNS inflammation. To directly address the role of CD26/DP IV in vivo, we examined Th1 immune responses and susceptibility to experimental autoimmune encephalomyelitis in CD26−/− mice. We show that gene deletion of CD26 in mice leads to deregulation of Th1 immune responses. Although production of IFN-γ and TNF-α by pathogenic T cells in response to myelin Ag was enhanced in CD26−/− mice, production of the immunosuppressive cytokine TGF-β1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-β1 production, responsiveness to external TGF-β1 was normal in T cells from CD26−/− mice, excluding alterations in TGF-β1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-β1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-β1 production in T cells from CD26−/− mice. The striking functional deregulation of Th1 immunity was also seen in vivo. Thus, clinical experimental autoimmune encephalomyelitis scores were significantly increased in CD26−/− mice immunized with peptide from myelin oligodendrocyte glycoprotein. These results identify CD26/DP IV as a nonredundant inhibitory receptor controlling T cell activation and Th1-mediated autoimmunity, and may have important therapeutic implications for the treatment of autoimmune CNS disease.

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Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225

Cited by 48 publications

References 15 publications

Emerging roles of serine proteinases in tissue turnover in arthritis

Emerging roles of serine proteinases in tissue turnover in arthritis

Circulating CD26 Is Negatively Associated with Inflammation in Human and Experimental Arthritis

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

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