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Equine veterinary journal2016; 49(4); 539-544; doi: 10.1111/evj.12647

Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

Abstract: Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. Objective: To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Methods: Experimental controlled study. Methods: Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Results: Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. Conclusions: This study examined MSC death in vitro only and utilized antisera from a small number of horses. Conclusions: The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death.
© 2016 The Authors Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.
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Publication Date: 2016-12-13 PubMed ID: 27862236PubMed Central: PMC5425313DOI: 10.1111/evj.12647Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study investigates the potential immune response in horses to allogeneic mesenchymal stem cells (MSCs) which are mismatched to the recipient’s major histocompatibility complex (MHC). It suggests that such mismatches could lead to the stem cells being recognized by the recipient’s immune system and targeted for elimination, thus reducing the efficacy of the treatment.

Methods Involved

  • The scientists performed a controlled experiment where antisera collected from four horses injected with MHC-mismatched stem cells were incubated with ELA-A2 MSCs and complement (a component of the immune system). Cell death was then analysed.
  • A control horse was also injected with MHC-matched MSCs for comparison.
  • Next, the researchers performed microcytotoxicity assays, where cells are tested for their susceptibility to death by immune factors.
  • The experiments involved evaluating the effect of antisera on the cells at different time points post-injection.
  • Peripheral blood leukocytes (PBLs) that shared the ELA-A2 haplotype served as a positive control, given their known reaction with MHC antibodies.

Research Findings

  • Antisera from all four horses that were injected with MHC-mismatched MSCs contained antibodies which killed the MSCs.
  • It was observed that in two out of the four horses, the antibodies were present as early as one week post-injection.
  • The level of MSC death was comparable to that of the PBLs at all times.
  • Importantly, the control horse, which received MHC-matched MSCs, did not produce cytotoxic antibodies at any time.

Research Conclusions

  • The researchers concluded that MHC-mismatched MSCs could induce an antibody response that can kill the stem cells in vitro.
  • Therefore, caution is advised when using MHC-mismatched MSCs for therapeutic purposes, as it could lead to reduced efficacy due to targeted stem cell death.
  • However, it was also stated that the results were based on a small number of horses and the study only examined stem cell death in vitro. Therefore, further investigations are necessary to fully understand implications in a clinical setting.

Cite This Article

APA
Berglund AK, Schnabel LV. (2016). Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies. Equine Vet J, 49(4), 539-544. https://doi.org/10.1111/evj.12647

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 49
Issue: 4
Pages: 539-544

Researcher Affiliations

Berglund, A K
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Schnabel, L V
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.

MeSH Terms

  • Animals
  • Antibodies / immunology
  • Antibody Formation / immunology
  • Bone Marrow
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Horses
  • Major Histocompatibility Complex / immunology
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / immunology

Grant Funding

  • K08 AR060875 / NIAMS NIH HHS

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