title: 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.
abstract: 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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nataraju
authors.initials: N
authors.lastname: Angaswamy
authors.forename: Naohiko
authors.initials: N
authors.lastname: Fukami
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: George J
authors.initials: GJ
authors.lastname: Cianciolo
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011687:Purines / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C511928:2-amino-6-chloro-9-((5-dihydroxyboryl)pentyl)purine; D001896:Boron Compounds; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011687:Purines; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016572:Cyclosporine; D013482:Superoxide Dismutase