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Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.
Abstract: This study tested the hypothesis that Major Histocompatibility Complex (MHC) incompatible equine mesenchymal stromal cells (MSCs) would induce cytotoxic antibodies to donor MHC antigens in recipient horses after intradermal injection. No studies to date have explored recipient antibody responses to allogeneic donor MSC transplantation in the horse. This information is critical because the horse is a valuable species for assessing the safety and efficacy of MSC treatment prior to human clinical application. Methods: Six MHC heterozygote horses were identified as non-ELA-A2 haplotype by microsatellite typing and used as allogeneic MHC-mismatched MSC recipients. MHC homozygote horses of known ELA-A2 haplotype were used as MSC and peripheral blood leukocyte (PBL) donors. One MHC homozygote horse of the ELA-A2 haplotype was the recipient of ELA-A2 donor MSCs as an MHC-matched control. Donor MSCs, which were previously isolated and immunophenotyped, were thawed and culture expanded to achieve between 30x10(6) and 50x10(6) cells for intradermal injection into the recipient's neck. Recipient serum was collected and tested for the presence of anti-donor antibodies prior to MSC injection and every 7Â days after MSC injection for the duration of the 8-week study using the standard two-stage lymphocyte microcytotoxicity dye-exclusion test. In addition to anti-ELA-A2 antibodies, recipient serum was examined for the presence of cross-reactive antibodies including anti-ELA-A3 and anti-RBC antibodies. Results: All MHC-mismatched recipient horses produced anti-ELA-A2 antibodies following injection of ELA-A2 MSCs and developed a wheal at the injection site that persisted for the duration of the experiment. Anti-ELA-A2 antibody responses were varied both in terms of strength and timing. Four recipient horses had high-titered anti-ELA-A2 antibody responses resulting in greater than 80% donor PBL death in the microcytotoxicity assays and one of these horses also developed antibodies that cross-reacted when tested on lymphocyte targets from a horse with an unrelated MHC type. Conclusions: Allogeneic MSCs are capable of eliciting antibody responses in vivo that can be strong and also cross-reactive with MHC types other than that of the donor. Such responses could limit the effectiveness of repeated allogeneic MSC use in a single horse, and could also result in untoward inflammatory responses in recipients.
Publication Date: 2015-04-12 PubMed ID: 25889095PubMed Central: PMC4414005DOI: 10.1186/s13287-015-0053-xGoogle Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
- Antibodies
- Clinical Study
- Diagnosis
- Disease Diagnosis
- Disease Treatment
- Equine Diseases
- Equine Health
- Experimental Methods
- Genetics
- Genotyping
- Horses
- Immune Response
- Immunology
- In Vivo
- Inflammation
- Major Histocompatibility Complex (MHC)
- Mesenchymal Cells
- Microsatellites
- Stem Cells
- Veterinary Medicine
- Veterinary Research
Summary
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This research studied the immune responses of recipient horses to the intradermal transplant of Major Histocompatibility Complex (MHC) incompatible equine mesenchymal stromal cells, finding that the transplants can elicit strong, potentially cross-reactive, antibody responses that could limit the effectiveness of repeated treatments.
Objectives and Methodologies
- The primary objective of this study was to investigate the immunological reactions of horses when they receive a transplant of MHC incompatible equine mesenchymal stromal cells (MSCs). The researchers particularly wanted to determine any induced cytotoxic antibodies to the donor MHC antigens. The study sought to fill a research gap as no previous studies had examined potential antibody responses to allogeneic donor MSC transplantation in horses.
- Six MHC heterozygote horses were selected as recipients for the transplanted cells, while MHC homozygote horses were used as cell and peripheral blood leukocyte donors. Donor cells had been previously isolated and immunophenotyped, and were subsequently culture-expanded to a quantity suitable for intradermal injection into the recipient horses’ neck.
- Recipient horse serum was tested for the presence of anti-donor antibodies before the MSC injection and weekly thereafter for eight weeks. The researchers applied the two-stage lymphocyte microcytotoxicity dye-exclusion test method.
Results
- All MHC-mismatched recipient horses displayed anti-ELA-A2 antibodies following injection with ELA-A2 MSCs and developed a persistent wheal at the injection site.
- Anti-ELA-A2 antibody responses varied in strength and timing among the horses. Four of them had high-titered anti-ELA-A2 antibody responses that caused more than 80 percent donor PBL death in the microcytotoxicity assays.
- One of these four horses showed remarkable cross-reactivity as it produced antibodies that reacted to lymphocyte targets from a horse with an unrelated MHC type.
Conclusion
- Allogeneic MSCs have the potential to elicit in vivo antibody responses. They can be strong and cross-reactive with MHC types that are distinct from that of the donor.
- This may limit the efficacy of repeated allogeneic MSC use in a single horse and it could also trigger unwanted inflammatory responses in the recipients.
Cite This Article
APA
Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D, Schnabel LV.
(2015).
Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.
Stem Cell Res Ther, 6(1), 54.
https://doi.org/10.1186/s13287-015-0053-x Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. lmp238@cornell.edu.
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. laf4@cornell.edu.
- Baker Institute for Animal Health, Cornell University, Ithaca, NY, 14853, USA. dfa1@cornell.edu.
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. jmc292@cornell.edu.
- Baker Institute for Animal Health, Cornell University, Ithaca, NY, 14853, USA. mmb263@cornell.edu.
- Baker Institute for Animal Health, Cornell University, Ithaca, NY, 14853, USA. dm96@cornell.edu.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA. lauren_schnabel@ncsu.edu.
MeSH Terms
- Animals
- Antibodies / immunology
- Antibody Formation / immunology
- Bone Marrow Cells / cytology
- Bone Marrow Cells / immunology
- Female
- Horses
- Inflammation / immunology
- Major Histocompatibility Complex / immunology
- Male
- Mesenchymal Stem Cell Transplantation / methods
- Mesenchymal Stem Cells / immunology
- Transplantation, Homologous / methods
Grant Funding
- K08 AR060875 / NIAMS NIH HHS
- 1K08AR060875 / NIAMS NIH HHS
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