Cell-dose−dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs

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.