Pharmacologically Induced Regression of Chronic Transplant Rejection

Xiao, Fei; Chong, Anita S.; Shen, Jikun; Yang, Jiamei; Short, Jenny L; Foster, Patricia L.; Sankary, Howard; Jensik, Stephen C.; Mital, Deepak; McChesney, Lawrence

doi:10.1097/00007890-199511270-00001

Cited by 55 publications

(29 citation statements)

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“…It also prevents the proliferation of B cells and Ab production by B cells (2). How leflunomide suppresses transplant rejection (7)(8)(9), adjuvant arthritis (1), proliferation of B and T cells and smooth muscle cells (6,7,10), and IL-2R expression (6) is not understood, but a role for inhibition of NF-B activation has been suggested (11).…”

Section: Eflunomide (Hwa-486) or N-(4-trifluoromethylphenyl)-mentioning

confidence: 99%

Leflunomide Suppresses TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis

Manna

Mukhopadhyay

Aggarwal

2000

The Journal of Immunology

179

110

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Leflunomide is a pyrimidine biosynthesis inhibitor that has recently been approved for treatment of rheumatoid arthritis. However, the mechanism of leflunomide’s antiarthritis activity and is not fully understood. The critical role that TNF plays in rheumatoid arthritis led us to postulate that leflunomide blocks TNF signaling. Previously, we have demonstrated that leflunomide inhibits TNF-induced NF-κB activation by suppressing I-κBα (inhibitory subunit of NF-κB) degradation. We in this study show that leflunomide also blocks NF-κB reporter gene expression induced by TNFR1, TNFR-associated factor 2, and NF-κB-inducing kinase (NIK), but not that activated by the p65 subunit of NF-κB, suggesting that leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced phosphorylation of I-κBα, as well as activation of I-κBα kinase-β located downstream to NIK. Leflunomide also inhibited TNF-induced activation of AP-1 and the c-Jun N-terminal protein kinase activation. TNF-mediated cytotoxicity and caspase-induced poly(ADP-ribose) polymerase cleavage were also completely abrogated by treatment of Jurkat T cells with leflunomide. Leflunomide suppressed TNF-induced reactive oxygen intermediate generation and lipid peroxidation, which may explain most of its effects on TNF signaling. The suppressive effects of leflunomide on TNF signaling were completely reversible by uridine, indicating a critical role for pyrimidine biosynthesis in TNF-mediated cellular responses. Overall, our results suggest that suppression of TNF signaling is one of the possible mechanisms for inhibitory activity of leflunomide against rheumatoid arthritis.

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Section: Eflunomide (Hwa-486) or N-(4-trifluoromethylphenyl)-mentioning

confidence: 99%

Leflunomide Suppresses TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis

Manna

Mukhopadhyay

Aggarwal

2000

The Journal of Immunology

179

110

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“…PSIs may also inhibit proliferation of fibroblasts and smooth muscle cells at least partly through interaction with growth factors, such as, fibroblast growth factor (FGF) (6,7). Through their combined effect on immunity and fibrosis, these agents may, therefore, inhibit CAV development or progression.…”

Section: Introductionmentioning

confidence: 99%

Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial

Arora

Erikstad

Ueland

et al. 2012

American Journal of Transplantation

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Clinical trial registry: Clinicaltrials.gov (unique registration number NCT00377962)In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNItherapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

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“…We already have at our disposal a few experimental studies testing leflunomide on chronic or acute graft rejection (Williams et al 1994;Xiao et al 1995;Shen et al 1998). More recently the inhibitory effects of leflunomide upon HSV, CMV and BK virus have been proved in vitro like in vivo Knight et al 2001;Farasati et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Leflunomide an Immunosuppressive Drug for Antiviral Purpose in Treatment for BK Virus-Associated Nephropathy After Kidney Transplantation

Bazin¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Pharmacologically Induced Regression of Chronic Transplant Rejection

Cited by 55 publications

References 0 publications

Leflunomide Suppresses TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis

Leflunomide Suppresses TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis

Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial

Leflunomide an Immunosuppressive Drug for Antiviral Purpose in Treatment for BK Virus-Associated Nephropathy After Kidney Transplantation

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