Humoral immune response to equine mesenchymal stem/stromal cells (MSCs): MHC compatibility has more influence than...

Mesenchymal stem/stromal cells (MSCs) hold great potential for treating various conditions, but their effectiveness and safety in allogeneic therapies can be affected by the recipient's immune response, among other factors. Allogeneic MSC administration has been associated with immune recognition in different species, including horses. These animals are both veterinary patients and translational models, offering valuable insights into how allogeneic MSCs interact with the immune system in vivo. Factors such as inflammation, chondrogenic differentiation, and major histocompatibility complex (MHC) compatibility between donor and recipient can influence immune responses, potentially affecting the feasibility of repeated MSC administrations. This study evaluates the humoral immune response following repeated administration of chondrogenically differentiated (MSC-chondro), pro-inflammatory primed (MSC-primed), and basal (MSC-naïve) equine MSCs into autologous, MHC-matched, and MHC-mismatched recipients.

Equine MSC-chondro, MSC-primed or MSC-naïve were embedded into alginate scaffolds and repeatedly implanted subcutaneously into autologous, MHC-matched or MHC-mismatched allogeneic horse recipients. Serum samples collected before and 1, 3, and 6 weeks after each administration were analysed for cytotoxic allo-antibodies against donor MHC. Recipient sera (neat, 1:2 and 1:16 dilution) were tested against donor-derived target cells using two-stage microcytotoxicity assays.

Autologous and MHC-matched recipients did not develop antibodies against the MHC of the donor, regardless of the MSC type administered. In contrast, MHC-mismatched horses developed allo-antibodies after the first administration, with a notable increase following the second administration. All the MSC types triggered a humoral immune response in MHC-mismatched recipients, but MSC-chondro provoked the strongest immune recognition.

Donor-recipient MHC compatibility was more important than inflammatory priming or chondrogenic differentiation of equine MSCs to prevent the development of allo-antibodies. Thus, when donor and recipient are MHC-matched, different types of equine MSCs (MSC-chondro, MSC-primed or MSC-naïve) could be administered without producing a humoral response.