LMP-420, a Small Molecular Inhibitor of TNF-α, Prolongs Islet Allograft Survival by Induction of Suppressor of Cytokine Signaling-1: Synergistic Effect with Cyclosporin-A

• Published in: Cell Transplantation 2012-01, Vol.21 (6), p.1285-1296
• Main Authors: Angaswamy, Nataraju, Fukami, Naohiko, Tiriveedhi, Venkataswarup, Cianciolo, George J., Mohanakumar, T.
• Format: Article
• Language: English
• Subjects: Animals; Boron Compounds - pharmacology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cyclosporine - pharmacology; Graft Survival - drug effects; Immunohistochemistry; Immunosuppressive Agents - pharmacology; Interleukin-10 - metabolism; Interleukin-2 - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Islets of Langerhans Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Purines - pharmacology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Transplantation, Homologous; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368911X637371

Inflammatory insults following islet transplantation (ITx) hinders engraftment and long-term function of the transplanted (Tx) islets. Using a murine model of ITx, we determined the role of LMP-420, a novel TNF-α inhibitor, both individually and in combination with the immunosuppressant cyclosporine A (CSA) in islet engraftment and survival. Diabetic C57BL/6 mice were Tx with 500 BALB/c islets under the kidney capsule. Four cohorts were used: LMP-420 only, CSA only, combination of LMP-420 and CSA (LMP+CSA), and control (n = 12 per cohort). Serial monitoring of blood glucose levels revealed that LMP+CSA (35 ± 5 days) prolonged stable blood insulin levels compared to control (6 ± 4 days). Immunohistology demonstrated that coadministration (LMP+CSA) results in a significant decrease in CD8+ T-cell infiltration (LMP+CSA: 31 ± 18 vs. control: 224 ± 51 cells, p < 0.001). Serum cytokine analysis revealed that LMP-420 administration resulted in an increase in the anti-inflammatory cytokine IL-10 (2.5-fold), and a decrease in TNF-α (threefold) with no change in IL-2. However, coadministration resulted in a marked decrease in both IL-2 and TNF-α (threefold) along with increase in IL-10 (threefold). Coadministration also demonstrated increase of antiapoptotic SOCS-1 and Mn-SOD expression and significant reduction of donor-specific antibodies (p < 0.005). In conclusion, LMP-420 administration with CSA results in the upregulation of anti-inflammatory and antiapoptotic mechanisms which facilitate islet allograft engraftment and survival.