Allo-antibody production after intraarticular administration of mesenchymal stem cells (MSCs) in an equine osteoarthritis model: effect of repeated administration, MSC inflammatory stimulation, and equine leukocyte antigen (ELA) compatibility

Abstract

Background Antibody production after allogeneic administration of mesenchymal stem cells (MSCs) could impact their clinical application. Proinflammatory priming of MSCs can potentiate their regulatory ability in vivo but increased expression of major histocompatibility complex (MHC) might augment their immunogenicity, potentially leading to immune memory thus limiting repeated allogeneic administration. This study aimed at evaluating the production of cytotoxic allo-antibodies directed against donor’s ELA (equine leukocyte antigen) in mismatched and halfmatched horses receiving repeated intraarticular administration of stimulated MSCs (MSC-primed) and unstimulated MSCs (MSC-naïve) in pathologic joints. Methods From available stored samples from a previous in vivo study, cells from one donor and serially collected sera (five time-points) from three groups of recipients were used based on their ELA haplotypes to perform microcytotoxicity assays: Group 1 recipients mismatched with the donor that received MSC-naïve (naïve-mismatched recipients); Group 2 recipients mismatched with the donor that received MSC-primed (primed-mismatched recipients); Group 3 recipients halfmatched with the donor (sharing 1/2 haplotypes) that received MSC-primed (primed-halfmatched recipients). Sera from recipients (neat, 1:2 and 1:16 dilution) were tested against target cells from the donor (cryopreserved and expanded MSC-naïve and MSC-primed) or from one animal presenting the same ELA haplotypes than the donor (fresh peripheral blood lymphocytes as control). Results One to three weeks after first MSC administration, all recipient groups produced allo-antibodies regardless of MSC received (naïve or primed) and matching degree with donor. However, secondary response after MSC re-exposure was less evident in halfmatched recipients (MSC-primed) than in mismatched ones (both MSC-naïve and MSC-primed). Recipients of MSC-primed (both mismatched and halfmatched) tended towards developing lower antibody response than MSC-naïve recipients in vivo, but MSC-primed were targeted to death in higher percentage in vitro in the microcytoxicity assay. Conclusions After first intraarticular allogeneic administration, the immunomodulatory profile of MSC-primed would have led to lower antibody production, but these antibodies would target more easily MSC-primed after second injection (re-exposure), likely because of their higher MHC expression.

The proangiogenic effects of extracellular vesicles secreted by dental pulp stem cells derived from periodontally compromised teeth

“…Although DPSCs can be isolated from exfoliated deciduous teeth, extracted wisdom teeth, and sometimes teeth extracted for orthodontic reasons [2,5], we still cannot ensure that a patient will have a tooth available for cell isolation when cell therapy is needed. In this context, stem cells from allogeneic tissues might be an alternative choice, but the use of allogeneic MSCs adds additional safety and ethical concerns [9]. In view of this, scientists have sought to use DPSCs derived from inflamed pulp tissues, as these tissues are more easily accessible in clinics and often can be obtained from teeth with crown fractures [10], irreversible pulpitis [11][12][13], and periodontitis [14,15].…”

Interactions Between Allogeneic Mesenchymal Stromal Cells and the Recipient Immune System: A Comparative Review With Relevance to Equine Outcomes

“…Resounding immunosuppressive effects are seen when MSCs are mixed with activated neutrophils or activated lymphocytes ( 10 , 11 , 13 , 28 – 31 , 65 ). Allogeneic MSCs are recognized by the innate and adaptive arms of the immune system and their viability may be decreased following immune recognition ( 62 , 64 , 71 ). An antibody response is generated post-injection in the horse which likely would inhibit their therapeutic efficacy upon repeat treatment ( 32 , 62 , 64 , 103 ).…”

“…Few studies have been completed to determine if repeat administration of allogeneic MSCs is more beneficial than a single treatment. As we have detailed, there would likely be antibody presence in the animal upon repeat treatment along with memory Tcells ( 62 , 71 , 75 ). Repeat treatment using allogeneic MSCs has shown to cause an increase in leukocyte recruitment when used intra-articularly ( 32 ).…”

“…Conversely, some MSCs do not express MHC II antigens, while others have a strong positive expression ( 49 , 59 ). Most problematically, MHC I and II expression is increased in the face of culture with foreign lymphocytes, when MSCs are cultured with inflammatory cytokines, or as the MSCs differentiate ( 46 , 60 – 62 ). The expression of MHC I and II motifs on MSCs are important in that they are the key cell markers utilized for alloimmunity by the host's immune system, and expression of these markers identifies the MSCs as targets for destruction.…”

“…There is significant antibody production to allogeneic MSCs across species ( 71 , 76 , 77 ). Barrachina et al ( 62 ) found that all equine patients receiving intra-articular allogeneic mis-matched MSCs formed antibodies after injection. Pezzanite et al ( 71 ) used MSCs of a mis-matched ELA haplotype and injected these cells intradermally in horses.…”