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

• Published in: PloS one 2019-11, Vol.14 (11), p.e0225624-e0225624
• Main Authors: Khattar, Mithun, Baum, Caitlin E, Schroder, Paul, Breidenbach, Joshua D, Haller, Steven T, Chen, Wenhao, Stepkowski, Stanislaw
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Arthritis; Autoimmunity; Basic-Leucine Zipper Transcription Factors - deficiency; Basic-Leucine Zipper Transcription Factors - genetics; Biology and Life Sciences; Coronary vessels; Cytokines; Fc receptors; Fusion protein; Graft rejection; Graft Rejection - etiology; Graft Rejection - immunology; Grafting; Grafts; Heart; Heart transplantation; Heart Transplantation - adverse effects; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Immunization; Immunology; Interferon-gamma - metabolism; Interleukin 21; Interleukins - deficiency; Interleukins - genetics; Laboratory animals; Life sciences; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical schools; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Pulmonary arteries; Receptors, Interleukin-21 - genetics; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - biosynthesis; Rejection; Signaling; Skin; Skin grafts; Skin Transplantation - adverse effects; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription factors; Transplantation, Homologous - adverse effects; Transplants & implants; Vascular diseases; Vascular Diseases - etiology; Vascular Diseases - prevention & control; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0225624

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.