A Small Molecule ?2 Integrin Agonist Improves Chronic Kidney Allograft Survival by Reducing Leukocyte Recruitment and Accompanying Vasculopathy.

ABSTRACT: Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2(b)) recipients received kidney allografts from Balb/c mice (H-2(d)). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2?weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52?±?0.18?mg/dL vs 0.24?±?0.07?mg/dL (n?=?5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3?+ Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.

SUBMITTER: Khan SQ 

PROVIDER: S-EPMC4291902 | biostudies-other | 2014

REPOSITORIES: biostudies-other