Anti‐donor antibody induction following intramuscular injections of allogeneic mesenchymal stromal cells

Senthilkumar Alagesan, Clara Sanz‐Nogués, Xizhe Chen, Michael Creane, Thomas Ritter, Rhodri Ceredig, Timothy O'Brien, Matthew D Griffin

Allogeneic mesenchymal stromal cells (allo-MSC) are a promising "off-the-shelf" therapy with anti-inflammatory and pro-repair properties. This study investigated humoral immune responses to intramuscular (IM) injections of allo-MSC. Total and isotype-specific anti-donor IgG and donor-specific complement-mediated lysis were determined in sera from healthy mice two weeks after single or repeated IM injections of fully-MHC-mismatched allo-MSC with comparison to mice receiving syngeneic MSC, allogeneic splenocytes or saline. In mice subjected to hind limb ischemia (HLI), anti-donor IgG was analysed following IM allo-MSC injection with and without administration of the T-cell immunosuppressant tacrolimus. Recipients of single and repeated IM allo-MSC developed readily-detectable anti-donor IgG. Serum anti-donor IgG levels were similar to those of allo-splencoyte recipients but had higher IgG1/IgG2a ratio and variable capacity for complement-mediated lysis of donor cells. The induced anti-donor IgG bound readily to allo-MSC and this binding was increased following allo-MSC pre-treatment with interferon gamma. In mouse with HLI, IM injection of allo-MSC into the ischemic limb was also associated with induction of anti-donor IgG but this was abrogated by tacrolimus. The results indicate that allo-MSC are inherently immunogenic when delivered intramuscularly to healthy and ischemic mouse hind limb but induce an IgG1-skewed humoral response that is suppressed by tacrolimus. This article is protected by copyright. All rights reserved.