Small molecule agonists of CD11b/CD18 reduce leukocyte activation and recruitment to promote kidney allograft survival (TRAN3P.909)

Allograft rejection in kidney transplantation is associated with leukocyte infiltration, including myeloid cells expressing β2 integrin CD11b/CD18. We reported that activation of CD11b/CD18 by a small molecule compound, leukadherin-1 (LA1), increases leukocyte cell adhesion to the inflamed endothelium, prevents transmigration and inhibits leukocyte tissue recruitment resulting in improved kidney function in a murine nephritis model. Here we test whether LA1 mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplant, where C57BL/6J (H-2b) recipients received a kidney allograft from Balb/c mice (H-2d). Control recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received standard CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. Renal allograft rejection was considered when mice displayed signs of ill health and high serum creatinine levels. Combination therapy reduced leukocyte infiltration and neointimal hyperplasia and increased graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. At week 5, CsA treated controls had serum creatinine values of 0.6 mg/dl while LA1 and CsA treated mice had baseline values of 0.2 mg/dl. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify leukadherins as therapeutic agents for renal transplantation.