HOW DO INFLAMMATION, DIFFERENTIATION, AND MHC COMPATIBILITY AFFECT THE IMMUNOGENICITY AND IMMUNOMODULATORY POTENTIAL OF EQUINE MESENCHYMAL STEM CELLS (MSCs)?

Jul 1, 2022, 12:00 PM
10m
Room: S3 B

Room: S3 B

Speaker

Cequier Soler, Alina (Laboratorio de Genética Bioquímica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragón– IA2 - (Universidad de Zaragoza-CITA); Instituto de Investigación Sanitaria de Aragón (IIS), Zaragoza, 50013, Spain Servicio de Cirugía y Medicina)

Description

Introduction:
Immunomodulation and immunogenicity of mesenchymal stem cells (MSCs) may influence their efficacy and safety, thus being key for their therapeutic use. The immune regulatory mechanisms of MSCs depend mostly on the secretion of different mediators which are not only important for the MSC therapeutic mechanisms but also to facilitate their escape from immune recognition when administered allogeneically. Actually, a highly relevant paradigm change is that MSCs are not truly immune-privileged but immune-evasive, and thus, their recognition and elimination by the immune system in the allogeneic setting should be considered. Since the horse is highly valuable as both patient and translational model, further knowledge on equine MSC immune properties is required. This study analyzed how inflammation, chondrogenic differentiation and compatibility for the major histocompatibility complex (MHC) influence the MSC immunomodulatory-immunogenicity balance by studying the changes elicited in vitro by equine MSCs on relevant lymphocyte subpopulations.

Methodology:
Equine MSCs in basal conditions, pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) were co-cultured with either autologous or allogeneic MHC-matched/mismatched lymphocytes. Two types of co-cultures were used: immunosuppressive assays to study MSC immunomodulatory potential, and one-way modified mixed leukocyte reactions (MLRs) to assess MSC immunogenicity. Lymphocytes were stained with carboxyfluorescein succinimidyl ester (CFSE) and with a panel of antibodies to study changes in the frequency and proliferation of T cell subsets (cytotoxic, helper and regulatory) and B cells by flow cytometry.

Results:
Overall, MSC-primed were superior suppressing the proliferation of lymphocytes, followed by MSC-chondro and MSC-naïve. The proliferation of CD3+ T cells was reduced in the presence of all types of MSCs and for all the combinations (autologous and allogeneic MHC-matched and mismatched). When looking at specific lymphocyte subsets, MSC-primed showed higher regulatory potential of the proliferation of cytotoxic and helper T cells and B cells, while inducing T reg cells in the one-way MLRs. However, MHC-mismatched MSC-primed can also elicit a proliferative response in lymphocytes likely due to increased MHC expression. Interestingly, equine MSC-chondro maintained their regulatory ability and did not increase their immunogenicity, but showed less capacity than MSC-primed to induce regulatory T cells and further stimulated B cell proliferation.

Conclusions:
Priming MSCs with proinflammatory cytokines activates their regulatory potential. However, inflammation can also increase the immune recognition of these cells through induction of MHC expression, thus making the allogeneic MHC-mismatched MSC-primed more likely to be targeted by the immune system. Importantly, equine MSCs do not lose their regulatory ability neither increase their immunogenicity after chondrogenic differentiation, but have reduced capacity to stimulate Treg cells and can stimulate the proliferation of B cells.
Even though lymphocyte proliferation assays are important tools to assess both the immunomodulatory and immune evasive properties of MSCs, subsequent in vivo studies are needed to elucidate the complex interactions between MSCs and the recipient immune system, which is critical to develop safe and effective therapies.
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