Cell-dose−dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs
Received 3 May 2010; received in revised form 16 June 2010; accepted 28 June 2010. published online 02 July 2010. Corrected Proof
Objective
Mesenchymal stem cells (MSCs) possess potent immunomodulatory activity, but whether they evade immune surveillance in an allogeneic transplant setting remains controversial. Herein we evaluated whether administration of major histocompatibility complex (MHC) class I−mismatched MSCs induce an immune response in rhesus macaques.
Materials and Methods
MSCs from a male donor were injected intracranially at two different doses into eight immunocompetent female infant rhesus macaques. Blood cell counts and circulating levels of lymphocyte subpopulations were quantified prior to surgery and at 10, 30, and 90 to 180 days postsurgery by flow cytometry. Immunoreactivity of recipient peripheral blood mononuclear cells to donor MSCs was evaluated in vitro and alloantibody production in vivo was determined by enzyme-linked immunosorbent assay and flow cytometry.
Results
MSC transplantation induced transient but significant increases in circulating white blood cells, lymphocytes, and neutrophils in most transplant recipients, but not sham-operated control animals. Flow cytometric analysis revealed a strong correlation between expansion of CD8+, CD16+, and CD8+/CD16+ lymphocyte subpopulations in peripheral blood, the dose of administered MSCs, and degree of antigenic mismatch between donor and recipient. MSC-specific alloantibodies were also detected in several transplant recipients. However, peripheral blood mononuclear cells harvested from transplant recipients postsurgery exhibited no lytic activity against donor MSCs in vitro upon rechallenge.
Conclusions
MSCs induced an allograft response in rhesus macaques that involved principally CD8+, CD16+, and CD8+/CD16+ lymphocyte subpopulations and was cell-dose− and haplotype-dependent. This study demonstrates that MSCs are weakly immunogenic in vivo when transplanted across MHC class I barriers.
aDepartment of Surgery, Tulane Medical School, New Orleans, La., USA
bDepartment of Veterinary Medicine, Tulane National Research Primate Center, Covington, La., USA
cDepartment of Immunology, Tulane National Research Primate Center, Covington, La., USA
dDepartment of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Fla., USA
Offprint requests to: Donald G. Phinney, Ph.D., Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, A213, Jupiter, FL 33458
ABSTRACT