title: A Small Molecule β2 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.
authors.affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.
authors.forename: Samia Q
authors.initials: SQ
authors.lastname: Khan
authors.affiliation: Department of Surgery, University of Alabama at Birmingham , Birmingham, AL , USA ; George M. O'Brien Kidney Research Center, University of Alabama at Birmingham , Birmingham, AL , USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Pathology, Rush University Medical Center , Chicago, IL , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cimbaluk
authors.affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.
authors.forename: Hatem
authors.initials: H
authors.lastname: Elshabrawy
authors.affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Jolly
authors.affiliation: Department of Surgery, University of Alabama at Birmingham , Birmingham, AL , USA ; George M. O'Brien Kidney Research Center, University of Alabama at Birmingham , Birmingham, AL , USA.
authors.forename: James F
authors.initials: JF
authors.lastname: George
authors.affiliation: George M. O'Brien Kidney Research Center, University of Alabama at Birmingham , Birmingham, AL , USA ; Department of Medicine, Division of Nephrology, University of Alabama at Birmingham , Birmingham, AL , USA.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
keywords: allograft; chronic rejection; inflammation; leukadherin; macrophage