Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo.
The emerging paradigm that MSCs are immune privileged has fostered the use of "off-the-shelf" allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo-immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients.
Center for Bioenvironmental Research, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
Iryna A
IA
Isakova
Department of Immunology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Calvin
C
Lanclos
Department of Immunology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Julie
J
Bruhn
Department of Immunology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Marcelo J
MJ
Kuroda
Department of Veterinary Medicine, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Kate C
KC
Baker
Kellogg School of Science and Technology, The Scripps Research Institute, Jupiter, Florida, United States of America ; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, United States of America.
Veena
V
Krishnappa
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, United States of America.
Donald G
DG
Phinney
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D006085:Graft Survival; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D008253:Macaca mulatta; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II