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Author Notes:

Correspondence: Jean Kwun jean.kwun@duke.edu

JK conceived the idea, designed experiments, and analyzed data.

JK and JP performed mouse experiments.

JK and JY performed in vitro experiments.

AF read pathology.

AK provided critical reagents and wrote the paper.

JK and SK wrote the paper.

We thank Drew Roenneburg (University of Wisconsin-Madison) for performing immunohistochemistry and Miriam Manook (Department of Surgery, King's college, UK) for critical manuscript review.

We also thank Stephanie Freel and Ashley Morgan for their critiques on the manuscript.

We also thank Sanofi S. A. for generously provided alemtuzumab for the study.

MHC Class I monomers were provided by the NIH Tetramer Core Facility.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

This work was supported by American Heart Association (AHA)/Enduring Heart Foundation Research Award 15SDG25710165 awarded to JK.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • IL-21
  • germinal center
  • follicular helper T cells
  • heart transplantation
  • antibody-mediated rejection
  • FOLLICULAR-HELPER-CELLS
  • KIDNEY-TRANSPLANT PATIENTS
  • GERMINAL CENTER FORMATION
  • T-CELLS
  • B-CELL
  • CARDIAC ALLOGRAFT
  • DE-NOVO
  • BRONCHIOLITIS OBLITERANS
  • RENAL-TRANSPLANTATION
  • ORGAN-TRANSPLANTATION

IL-21 Biased Alemtuzumab Induced Chronic Antibody-Mediated Rejection Is Reversed by LFA-1 Costimulation Blockade

Tools:

Journal Title:

Frontiers in Immunology

Volume:

Volume 9, Number OCT

Publisher:

, Pages 2323-2323

Type of Work:

Article | Final Publisher PDF

Abstract:

Despite its excellent efficacy in controlling T cell mediated acute rejection, lymphocyte depletion may promote a humoral response. While T cell repopulation after depletion has been evaluated in many aspects, the B cell response has not been fully elucidated. We tested the hypothesis that the mechanisms also involve skewed T helper phenotype after lymphocytic depletion. Post-transplant immune response was measured from alemtuzumab treated hCD52Tg cardiac allograft recipients with or without anti-LFA-1 mAb. Alemtuzumab induction promoted serum DSA, allo-B cells, and CAV in humanized CD52 transgenic (hCD52Tg) mice after heterotopic heart transplantation. Additional anti-LFA-1 mAb treatment resulted in reduced DSA (Fold increase 4.75 ± 6.9 vs. 0.7 ± 0.5; p < 0.01), allo-specific B cells (0.07 ± 0.06 vs. 0.006 ± 0.002 %; p < 0.01), neo-intimal hyperplasia (56 ± 14% vs. 23 ± 13%; p < 0.05), arterial disease (77.8 ± 14.2 vs. 25.8 ± 20.1%; p < 0.05), and fibrosis (15 ± 23.3 vs. 4.3 ± 1.65%; p < 0.05) in this alemtuzumab-induced chronic antibody-mediated rejection (CAMR) model. Surprisingly, elevated serum IL-21 levels in alemtuzumab-treated mice was reduced with LFA-1 blockade. In accordance with the increased serum IL-21 level, alemtuzumab treated mice showed hyperplastic germinal center (GC) development, while the supplemental anti-LFA-1 mAb significantly reduced the GC frequency and size. We report that the incomplete T cell depletion inside of the GC leads to a systemic IL-21 dominant milieu with hyperplastic GC formation and CAMR. Conventional immunosuppression, such as tacrolimus and rapamycin, failed to reverse AMR, while co-stimulation blockade with LFA-1 corrected the GC hyperplastic response. The identification of IL-21 driven chronic AMR elucidates a novel mechanism that suggests a therapeutic approach with cytolytic induction.

Copyright information:

Copyright © 2018 Kwun, Park, Yi, Farris, Kirk and Knechtle.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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