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: 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. 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). 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. 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.
Publication Date: 2020-02-07 PubMed ID: 32028995PubMed Central: PMC7006079DOI: 10.1186/s13287-020-1571-8Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Antibodies
- Cells
- Diagnosis
- Disease Diagnosis
- Disease Treatment
- Equine Diseases
- Equine Health
- Horses
- Immune Response
- Immune System
- Immunology
- In Vitro Research
- In Vivo
- Inflammation
- Intra-Articular Injection
- Major Histocompatibility Complex (MHC)
- Mesenchymal Cells
- Osteoarthritis
- Stem Cells
- Veterinary Medicine
- Veterinary Research
Summary
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The research paper investigates the formation of harmful allo-antibodies after the allogenic administration of Mesenchymal Stem Cells (MSCs) in an equine model of osteoarthritis. Assessments are made of the antibody responses following repeated administrations and stimulation of the MSCs, with evaluations as to the importance of the recipient and donor’s compatibility with Equine Leukocyte Antigen (ELA).
Understanding the Study
- The goal of the study was to determine the impact of allo-antibody production after allogeneic administration of MSCs, an important concern for their clinical application. Allo-antibodies are antibodies produced when an organism is exposed to cells or tissues from another member of the same species, which can potentially lead to adverse reactions.
- Mesenchymal Stem Cells (MSCs) are multipotent stem cells can differentiate into various cell types. They have characteristics that may potentially be used in the treatment of diseases such as osteoarthritis.
- Some factors, such as proinflammatory priming, can help improve MSC efficacy in vivo. However, they can also upregulate the expression of major histocompatibility complex (MHC), which might increase the production of allo-antibodies, leading to an immune response upon repeated administration.
Setting Up the Experiment
- The experiment involved the administration of MSCs in equine models suffering from osteoarthritis, in mismatched and halfmatched horses. It aimed to examine if there was allo-antibody production against the Equine Leukocyte Antigen (ELA) present in donor cells.
- Three different groups of recipient animals were created to examine the effects: mismatched recipients of MSC-naïve (new and unstressed MSCs); mismatched recipients of MSC-primed (proinflammatorily stimulated MSCs) and halfmatched recipients of MSC-primed.
- The sera from the recipient animals were tested against target cells from the donor animals (both MSC-naïve and MSC-primed) to evaluate the production of antibodies, using a microcytotoxicity assay which measures the percentage of dead cells from exposure to the serum.
Results of the Experiment
- The experiment found that allo-antibodies were developed by all recipient groups after the first administration of MSCs, irrespective of the form of MSCs and matching degree.
- The halfmatched recipients who received MSC-primed showed less secondary reaction, or antibody response, upon re-exposure to MSCs. This indicates that the ELA compatibility between the donor and recipient influences the immune response.
- The study also found evidence suggesting in initial MSC-primed administrations, there might be a lesser antibody response than to MSC-naïve. However, upon subsequent exposure, the MSC-primed might be more easily targeted for destruction by the immune system because of their higher MHC expression level.
Implications and Conclusions
- Overall, this research shows that allo-antibodies produced in response to allogeneic MSC injections can potentially limit the effectiveness of repeated MSC injections due to the body mounting an immune response.
- This shows that using MSCs in number of medical treatments might be problematic due to the allo-antibody generation, especially for repeated administration or mismatched donors.
- This research brings up questions about the most effective use of MSCs in treatment procedures, particularly around issues of compatibility, pre-treatment of MSCs (priming), and the schedule of administration.
Cite This Article
APA
Barrachina L, Cequier A, Romero A, Vitoria A, Zaragoza P, Vázquez FJ, Rodellar C.
(2020).
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.
Stem Cell Res Ther, 11(1), 52.
https://doi.org/10.1186/s13287-020-1571-8 Publication
Researcher Affiliations
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza - CITA, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza - CITA, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza - CITA, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
- Laboratorio de Genética Bioquímica LAGENBIO - Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain. rodellar@unizar.es.
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza - CITA, C/Miguel Servet, 177, 50013, Zaragoza, Spain. rodellar@unizar.es.
MeSH Terms
- Animals
- Disease Models, Animal
- Female
- Horses
- Immunomodulation / immunology
- Leukocytes / immunology
- Male
- Mesenchymal Stem Cell Transplantation / methods
- Mesenchymal Stem Cells / metabolism
- Osteoarthritis
Grant Funding
- AGL2017-84411-P / Ministerio de Economu00eda, Industria y Competitividad, Gobierno de Espau00f1a
- A19_17R / Gobierno de Aragu00f3n
- Pre-doctoral scholarship / Gobierno de Aragu00f3n
Conflict of Interest Statement
The authors declare that they have no competing interests.
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