Human interleukin‐10 delivered intrathecally by self‐complementary adeno‐associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine

Introduction Intrathecal interleukin (IL)‐10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL‐10 ortholog was tested. However, recent studies in swine testing porcine IL‐10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector‐encoded human IL‐10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity. Results Human IL‐10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti‐human IL‐10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. Conclusions The findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL‐10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL‐10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin‐10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL‐10 or related therapeutics may require syngeneic large animal models.