A small molecule β2 integrin agonist improves chronic kidney allograft survival by reducing leukocyte recruitment and accompanying vasculopathy

Samia Q. Khan, Lingling Guo, David J. Cimbaluk, Hatem Elshabrawy, Mohd Hafeez Faridi, Meenakshi Jolly, James F. George, Anupam Agarwal, Vineet Gupta

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalFrontiers in Medicine
Volume1
Issue numberNOV
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Allograft
  • Chronic rejection
  • Inflammation
  • Leukadherin
  • Macrophage

ASJC Scopus subject areas

  • General Medicine

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