Fibrinogen-like protein 2/fibroleukin induces long-term allograft survival in a rat model through regulatory B cells

• Published in: PloS one Vol. 10; no. 3; p. e0119686
• Main Authors: Bézie, Séverine, Picarda, Elodie, Tesson, Laurent, Renaudin, Karine, Durand, Justine, Ménoret, Séverine, Mérieau, Emmanuel, Chiffoleau, Elise, Guillonneau, Carole, Caron, Lise, Anegon, Ignacio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.03.2015; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Adoptive transfer; Allografts; Allografts - transplantation; Animals; B cells; B-Lymphocytes, Regulatory - metabolism; CD4 antigen; CD8 antigen; Cell proliferation; Cell survival; Dendritic cells; Fgl2 protein; Fibrin; Fibrinogen; Fibrinogen - administration & dosage; Fibrinogen - genetics; Gene expression; Gene transfer; Gene Transfer Techniques; Genomes; Graft rejection; Graft Rejection - genetics; Graft Rejection - metabolism; Graft Rejection - prevention & control; Graft Rejection - therapy; Graft Survival; Haplotypes; Heart; Heart diseases; Heart transplantation; Human health and pathology; Immunological tolerance; Immunoregulation; Iterative methods; Life Sciences; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Overexpression; Plasmids; Proteins; Rats; Rejection; Rodents; Splenocytes; Studies; Survival; T cells; Transplantation; Transplants & implants; Viruses; France; Norway
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119686

We previously described that in a rat model of heart transplantation tolerance was dependent on CD8+CD45RClow Tregs that over-expressed fibrinogen-like protein 2 (FGL2)/fibroleukin. Little is known on the immunoregulatory properties of FGL2. Here we analyzed the transplantation tolerance mechanisms that are present in Lewis 1A rats treated with FGL2. Over-expression of FGL2 in vivo through adenovirus associated virus -mediated gene transfer without any further treatment resulted in inhibition of cardiac allograft rejection. Adoptive cell transfer of splenocytes from FGL2-treated rats with long-term graft survival (> 80 days) in animals that were transplanted with cardiac allografts inhibited acute and chronic organ rejection in a donor-specific and transferable tolerance manner, since iterative adoptive transfer up to a sixth consecutive recipient resulted in transplantation tolerance. Adoptive cell transfer also efficiently inhibited anti-donor antibody production. Analysis of all possible cell populations among splenocytes revealed that B lymphocytes were sufficient for this adoptive cell tolerance. These B cells were also capable of inhibiting the proliferation of CD4+ T cells in response to allogeneic stimuli. Moreover, gene transfer of FGL2 in B cell deficient rats did not prolong graft survival. Thus, this is the first description of FGL2 resulting in long-term allograft survival. Furthermore, allograft tolerance was transferable and B cells were the main cells responsible for this effect.