Vascular Delivery of Allogeneic MuStem Cells in Dystrophic Dogs Requires Only Short-Term Immunosuppression to Avoid Host Immunity and Generate Clinical/Tissue Benefits

Judith Lorant (1, 2) , Thibaut Larcher (1, 2) , Nicolas Jaulin (3) , Benoit Hedan (4) , Aurélie Lardenois (1, 2) , Isabelle Leroux (1, 2) , Laurence Dubreil (1, 2) , Mireille Ledevin (1, 2) , Hélicia Goubin (1, 2) , Sophie Moullec (5) , Jack-Yves Deschamps (1, 2) , Chantal Thorin (5) , Catherine André (4) , Oumeya Adjali (3) , Karl Rouger (1, 2)

1 INRA - Institut National de la Recherche Agronomique
2 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
3 Inserm UMR 1089 - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques
4 IGDR - Institut de Génétique et Développement de Rennes
5 ONIRIS - École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique

Growing demonstrations of regenerative potential for some stem cells led recently to promising therapeutic proposals for neuromuscular diseases. We have shown that allogeneic MuStem cell transplantation into Golden Retriever muscular dystrophy (GRMD) dogs under continuous immunosuppression (IS) leads to persistent clinical stabilization and muscle repair. However, long-term IS in medical practice is associated with adverse effects raising safety concerns. Here, we investigate whether the IS removal or its restriction to the transplantation period could be considered. Dogs aged 4-5 months old received vascular infusions of allogeneic MuStem cells without IS (GRMD) or under transient IS (GRMD). At 5 months post-infusion, persisting clinical status improvement of the GRMD dogs was observed while GRMD dogs exhibited no benefit. Histologically, only 9-month-old GRMD dogs showed an increased muscle regenerative activity. A mixed cell reaction with the host peripheral blood mononucleated cells (PBMCs) and corresponding donor cells revealed undetectable to weak lymphocyte proliferation in GRMD dogs compared with a significant proliferation in GRMD dogs. Importantly, any dog group showed neither cellular nor humoral anti-dystrophin responses. Our results show that transient IS is necessary and sufficient to sustain allogeneic MuStem cell transplantation benefits and prevent host immunity. These findings provide useful critical insight to designing therapeutic strategies.

Mots clés: GRMD dog; immunosuppression; transplantation; cell therapy; Stem cells; Duchenne muscular dystrophy

Domaines: Génétique

Judith Lorant, Thibaut Larcher, Nicolas Jaulin, Benoit Hedan, Aurélie Lardenois, et al.. Vascular Delivery of Allogeneic MuStem Cells in Dystrophic Dogs Requires Only Short-Term Immunosuppression to Avoid Host Immunity and Generate Clinical/Tissue Benefits. Cell Transplantation, 2018, 27 (7), pp.1096-1110. ⟨10.1177/0963689718776306⟩. ⟨hal-01812518⟩