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

Cell Transplant. 2018 Jul;27(7):1096-1110. doi: 10.1177/0963689718776306. Epub 2018 Jun 5.

Abstract

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 (GRMDMU/no-IS) or under transient IS (GRMDMU/tr-IS). At 5 months post-infusion, persisting clinical status improvement of the GRMDMU/tr-IS dogs was observed while GRMDMU/no-IS dogs exhibited no benefit. Histologically, only 9-month-old GRMDMU/tr-IS 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 GRMDMU/tr-IS dogs compared with a significant proliferation in GRMDMU/no-IS 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.

Keywords: Duchenne muscular dystrophy; GRMD dog; Stem cells; cell therapy; immunosuppression; transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allogeneic Cells / immunology
  • Animals
  • Dog Diseases / therapy*
  • Dogs
  • Dystrophin / immunology
  • Immunosuppression / methods*
  • Male
  • Muscular Dystrophy, Animal / immunology
  • Muscular Dystrophy, Animal / therapy*
  • Stem Cell Transplantation / methods*
  • Stem Cells / cytology
  • Stem Cells / immunology
  • Transplantation, Homologous / methods

Substances

  • Dystrophin