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
  • Interleukin-21
  • 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