The systemic cellular immune response against allogeneic mesenchymal stem cells is influenced by inflammation, differentiation and MHC compatibility: in vivo study in the horse.
Abstract: The effectiveness and safety of allogeneic mesenchymal stem/stromal cells (MSCs) can be affected by patient's immune recognition. Thus, MSC immunogenicity and their immunomodulatory properties are crucial aspects for therapy. Immune responses after allogeneic MSC administration have been reported in different species, including equine. Interactions of allogenic MSCs with the recipient's immune system can be influenced by factors like matching or mismatching for the major histocompatibility complex (MHC) between donor-recipient, and by the levels of MHC expression in MSCs. The latter can vary upon MSC inflammatory exposure or differentiation, such as chondrogenic induction, making both priming and differentiation interesting therapeutic strategies. This study investigated the systemic immune cellular response against allogeneic equine MSCs in these situations. Either MSCs in basal conditions (MSC-naïve), pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) were repeatedly administered subcutaneously into autologous, MHC-matched or MHC-mismatched allogeneic equine recipients. At different time-points after each administration, lymphocytes were obtained from recipient horses and exposed to the same type of MSCs to assess the proliferative response of different T cell subsets (cytotoxic, helper, regulatory), B cells, and interferon gamma (IFNγ) secretion. Higher proliferative response of helper and cytotoxic T lymphocytes and IFNγ secretion was observed in response to all types of MHC-mismatched MSCs over MHC-matched ones. MSC-primed produced the highest immune response, followed by MSC-naïve, and MSC-chondro. However, MSC-primed activated Treg and had a mild effect on B cells, and the response after their second administration was similar to the first one. On the other hand, both MSC-chondro and MSC-naïve barely induced Treg response but promoted B lymphocyte activation, and proportionally induced a higher cell response after the second administration. In conclusion, both the type of MSC conditioning and the MHC compatibility influenced systemic immune recognition of equine MSCs after single and repeated administrations, but the response was different. Selecting MHC-matched donors would be particularly recommended for MSC-primed and repeated MSC-naïve administrations. While MHC-mismatching in MSC-chondro would be less critical, B cell response should not be ignored. Comprehensively investigating the immune response against equine allogeneic MSCs is crucial for advancing veterinary cell therapies.
Copyright © 2024 Cequier, Vázquez, Vitoria, Bernad, Fuente, Serrano, Zaragoza, Romero, Rodellar and Barrachina.
Publication Date: 2024-06-18 PubMed ID: 38957800PubMed Central: PMC11217187DOI: 10.3389/fvets.2024.1391872Google Scholar: Lookup
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- Journal Article
Summary
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This research investigates how stem cell therapies in horses are influenced by factors including inflammation, differentiation, and genetic compatibility. The results found each element can alter the immune response, which is important to consider when developing viable treatments.
Objective of the Research
- The research aims to understand how the immune response in horses changes when mesenchymal stem cells (MSCs) from another horse are introduced into the body. Crucially, it seeks to unravel whether factors like genetic compatibility and inflammation can impact how effective stem cell therapies are.
Methodology
- The study used equine MSCs in various states – basal condition (MSC-naive), inflamed (MSC-primed), or differentiated (MSC-chondro) – and injected them into horses that either had major histocompatibility complex (MHC) matched or mismatched to the donor cells.
- Researchers then observed the immune response at different times following each injection, specifically looking at proliferation of various T cell types, B cells, and the secretion of interferon gamma (IFNγ).
Findings
- The study found that MHC-mismatched MSCs led to a higher immune response than MHC-matched cells, with the primed cells creating the most significant effect, followed by the naive, then the differentiated cells.
- However, the primed cells also activated regulatory T cells and mildly triggered B cells, and this reaction was consistent across repeated injections.
- In contrast, both the naive and differentiated cells induced minimal regulatory T cell response but prompted B cell activation. The resultant cell response also increased after the second injection.
Conclusion and Implication
- The study concludes that both the condition of the MSCs and their MHC compatibility with the recipient can influence the immune system’s response. As such, in therapies involving repeated administration of naive cells or primed cells, it would be beneficial to use MHC-matched donors, while for differentiated cells MHC compatibility is less critical.
- However, the researchers suggest that the response of B cells should not be overlooked in these treatments. Detailed knowledge of these immune responses is key to advancing veterinary cell therapies, particularly those involving stem cells.
Cite This Article
APA
Cequier A, Vázquez FJ, Vitoria A, Bernad E, Fuente S, Serrano MB, Zaragoza MP, Romero A, Rodellar C, Barrachina L.
(2024).
The systemic cellular immune response against allogeneic mesenchymal stem cells is influenced by inflammation, differentiation and MHC compatibility: in vivo study in the horse.
Front Vet Sci, 11, 1391872.
https://doi.org/10.3389/fvets.2024.1391872 Publication
Researcher Affiliations
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Biochemical Genetics Laboratory LAGENBIO, Institute for Health Research Aragón (IIS), AgriFood Institute of Aragón (IA2), University of Zaragoza, Zaragoza, Spain.
- Equine Surgery and Medicine Service, Veterinary Hospital, University of Zaragoza, Zaragoza, Spain.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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