Fibrinogen-Like Protein 2/Fibroleukin Induces Long-Term Allograft Survival in a Rat Model through Regulatory B Cells

Séverine Bézie (1, 2) , Elodie Picarda (1, 2) , Laurent Tesson (1, 2) , Karine Renaudin (3) , Justine Durand (1, 2) , Séverine Ménoret (1, 2) , Emmanuel Mérieau (1, 2) , Elise Chiffoleau (1, 2) , Carole Guillonneau (1, 2) , Lise Caron (1, 2) , Ignacio Anegon (1, 2)

1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
2 ITUN - Institut de transplantation urologie-néphrologie
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes

We previously described that in a rat model of heart transplantation tolerance was dependent on CD8 + CD45RC low Tregs that over-expressed fibrinogen-like protein 2 (FGL2)/fibro-leukin. 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 transfer-able and B cells were the main cells responsible for this effect.

Domaines: Médecine humaine et pathologie

Séverine Bézie, Elodie Picarda, Laurent Tesson, Karine Renaudin, Justine Durand, et al.. Fibrinogen-Like Protein 2/Fibroleukin Induces Long-Term Allograft Survival in a Rat Model through Regulatory B Cells. PLoS ONE, 2015, 10 (3), pp.e0119686. ⟨10.1371/journal.pone.0119686⟩. ⟨inserm-02149009⟩