Interleukin 21 (IL-21) regulates chronic allograft vasculopathy (CAV) in murine heart allograft rejection

PLoS One. 2019 Nov 22;14(11):e0225624. doi: 10.1371/journal.pone.0225624. eCollection 2019.

Abstract

IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Graft Rejection / etiology*
  • Graft Rejection / immunology
  • Heart Transplantation / adverse effects*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Interferon-gamma / metabolism
  • Interleukins / deficiency
  • Interleukins / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-21 / genetics
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / biosynthesis
  • Skin Transplantation / adverse effects
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transplantation, Homologous / adverse effects*
  • Vascular Diseases / etiology*
  • Vascular Diseases / prevention & control

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Histocompatibility Antigens Class II
  • Interleukins
  • Receptors, Interleukin-21
  • Recombinant Fusion Proteins
  • Interferon-gamma
  • interleukin-21

Grant support

This work was funded by The University of Toledo Medical Microbiology and Immunology department. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.