Cell therapies2 hold promise in the development of treatments for neurodegenerative pathologies such as Huntington's disease. In such disorders, cell therapy may take the form of neuronal grafts in the brains of patients. Toward that goal, human pluripotent stem cells offer the advantages of renewability and specific differentiability into healthy and transplantable neurons potentially capable of alleviating and even eliminating symptoms in the graft recipient.
Huntington's disease is a rare, hereditary, genetic disease caused by a mutation in the gene carrying the code for a protein called huntingtin. The gene mutation results in an altered and toxic version of the protein, this latter in turn causing neuronal death in certain areas of the brain. Such loss of neurons results in a number of motor, psychiatric, behavioral and cognitive symptoms. Huntington's disease is currently incurable.
The objective of cell therapy in Huntington's disease is to replace damaged or lost neurons by neuronal grafts. However, the immunogenicity of the graft (its ability to provoke an immune response and rejection in the patient) is a major hurdle for the long-term success of this therapeutic approach.
Like in other tissue grafting settings, researchers are exploring histocompatible neuronal grafts, i.e., those derived from stem cells specifically selected for their histocompatibility with the patient. The hypothesis is that doing so will reduce the risk of rejection and thus the need for immunosuppressive treatments, which can cause potentially serious adverse effects such as infectious diseases and cancers.
To test that hypothesis, a consortium of European researchers transplanted neuronal grafts with different levels of histocompatibility into a primate model of Huntington's disease, that species being chosen for its immunological and physiological proximity to humans.
Their results show that in the absence of immunosuppression, graft histocompatibility alone cannot grant the long-term survival of the grafted neurons in the brain. Thus, it appears that continuous immunosuppression currently remains indispensable to prevent neuroinflammation and the risk of rejection in "allogeneic" grafts (those derived from stem cells of a healthy donor for transplantation into a sick patient) even when they are designed to be histocompatible. Without immunosuppression, such grafts are rejected after six months. Only "autologous" grafts, those derived from the patients themselves, are tolerated in the long-term.
The team's work points to the need for alternative strategies or complementary immunomodulation to ensure the survival -and thus the efficacy - cell therapies involving human stem cell-derived neuronal grafts for neurodegenerative diseases.
1 – MIRCen (Molecular Imaging Research Center, François Jacob Institute of Biology, CEA (Fontenay-aux-Roses); Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Inserm/UEVE UMR861, I-STEM, AFM Téléthon; Neurodegenerative Diseases Laboratory UMR9199, CNRS/CEA/Paris-Sud University/ Paris-Saclay University (Fontenay-aux-Roses); Stem Cell Research Center, I-STEM, AFM-Téléthon (Corbeil-Essonnes); CORIT, Padua University Hospital (Padua, Italy); Transplantation Immunology Unit, Padua University Hospital (Padua, Italy); Pathophysiology Center, Toulouse-Purpan, University of Toulouse/CNRS/Inserm/Paul Sabatier University (Toulouse).
2 - Cell therapy involves the grafting of cells to restore the function of a tissue or organ.