FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
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.
Get Full Text
Publication Date: 2016-12-13 PubMed ID: 27862236PubMed Central: PMC5425313DOI: 10.1111/evj.12647Google 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.
LinkedInCopy
  • 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

References

This article includes 31 references
  1. Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons.. J Orthop Res 2009 Oct;27(10):1392-8.
    pubmed: 19350658doi: 10.1002/jor.20887google scholar: lookup
  2. Crovace A, Lacitignola L, Rossi G, Francioso E. Histological and immunohistochemical evaluation of autologous cultured bone marrow mesenchymal stem cells and bone marrow mononucleated cells in collagenase-induced tendinitis of equine superficial digital flexor tendon.. Vet Med Int 2010;2010:250978.
    pmc: PMC2859019pubmed: 20445779doi: 10.4061/2010/250978google scholar: lookup
  3. Conze P, van Schie HT, van Weeren R, Staszyk C, Conrad S, Skutella T, Hopster K, Rohn K, Stadler P, Geburek F. Effect of autologous adipose tissue-derived mesenchymal stem cells on neovascularization of artificial equine tendon lesions.. Regen Med 2014;9(6):743-57.
    pubmed: 25431911doi: 10.2217/rme.14.55google scholar: lookup
  4. Ferris DJ, Frisbie DD, Kisiday JD, McIlwraith CW, Hague BA, Major MD, Schneider RK, Zubrod CJ, Kawcak CE, Goodrich LR. Clinical outcome after intra-articular administration of bone marrow derived mesenchymal stem cells in 33 horses with stifle injury.. Vet Surg 2014 Mar;43(3):255-65.
    pubmed: 24433318doi: 10.1111/j.1532-950x.2014.12100.xgoogle scholar: lookup
  5. Pacini S, Spinabella S, Trombi L, Fazzi R, Galimberti S, Dini F, Carlucci F, Petrini M. Suspension of bone marrow-derived undifferentiated mesenchymal stromal cells for repair of superficial digital flexor tendon in race horses.. Tissue Eng 2007 Dec;13(12):2949-55.
    pubmed: 17919069doi: 10.1089/ten.2007.0108google scholar: lookup
  6. Wilke MM, Nydam DV, Nixon AJ. Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model.. J Orthop Res 2007 Jul;25(7):913-25.
    pubmed: 17405160doi: 10.1002/jor.20382google scholar: lookup
  7. Caniglia CJ, Schramme MC, Smith RK. The effect of intralesional injection of bone marrow derived mesenchymal stem cells and bone marrow supernatant on collagen fibril size in a surgical model of equine superficial digital flexor tendonitis.. Equine Vet J 2012 Sep;44(5):587-93.
    pubmed: 22150794doi: 10.1111/j.2042-3306.2011.00514.xgoogle scholar: lookup
  8. Schnabel LV, Pezzanite LM, Antczak DF, Felippe MJ, Fortier LA. Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.. Stem Cell Res Ther 2014 Jan 24;5(1):13.
    pmc: PMC4055004pubmed: 24461709doi: 10.1186/scrt402google scholar: lookup
  9. Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D, Schnabel LV. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.. Stem Cell Res Ther 2015 Apr 12;6(1):54.
    pmc: PMC4414005pubmed: 25889095doi: 10.1186/s13287-015-0053-xgoogle scholar: lookup
  10. Carrade DD, Lame MW, Kent MS, Clark KC, Walker NJ, Borjesson DL. Comparative Analysis of the Immunomodulatory Properties of Equine Adult-Derived Mesenchymal Stem Cells().. Cell Med 2012;4(1):1-11.
    pmc: PMC3495591pubmed: 23152950doi: 10.3727/215517912x647217google scholar: lookup
  11. Paterson YZ, Rash N, Garvican ER, Paillot R, Guest DJ. Equine mesenchymal stromal cells and embryo-derived stem cells are immune privileged in vitro.. Stem Cell Res Ther 2014 Jul 30;5(4):90.
    pmc: PMC4247727pubmed: 25080326doi: 10.1186/scrt479google scholar: lookup
  12. Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL. Inflammatory effects of autologous, genetically modified autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses.. Vet Comp Orthop Traumatol 2013;26(6):453-60.
    pubmed: 24080668doi: 10.3415/vcot-13-01-0008google scholar: lookup
  13. Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL. Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses.. Vet Immunol Immunopathol 2013 Nov 15;156(1-2):99-106.
    pubmed: 24094688doi: 10.1016/j.vetimm.2013.09.003google scholar: lookup
  14. Ricco S, Renzi S, Del Bue M, Conti V, Merli E, Ramoni R, Lucarelli E, Gnudi G, Ferrari M, Grolli S. Allogeneic adipose tissue-derived mesenchymal stem cells in combination with platelet rich plasma are safe and effective in the therapy of superficial digital flexor tendonitis in the horse.. Int J Immunopathol Pharmacol 2013 Jan-Mar;26(1 Suppl):61-8.
    pubmed: 24046950doi: 10.1177/03946320130260s108google scholar: lookup
  15. Ardanaz N, Vázquez FJ, Romero A, Remacha AR, Barrachina L, Sanz A, Ranera B, Vitoria A, Albareda J, Prades M, Zaragoza P, Martín-Burriel I, Rodellar C. Inflammatory response to the administration of mesenchymal stem cells in an equine experimental model: effect of autologous, and single and repeat doses of pooled allogeneic cells in healthy joints.. BMC Vet Res 2016 Mar 31;12:65.
    pmc: PMC4815220pubmed: 27029614doi: 10.1186/s12917-016-0692-xgoogle scholar: lookup
  16. Kol A, Wood JA, Carrade Holt DD, Gillette JA, Bohannon-Worsley LK, Puchalski SM, Walker NJ, Clark KC, Watson JL, Borjesson DL. Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.. Stem Cell Res Ther 2015 Apr 15;6(1):73.
    pmc: PMC4446064pubmed: 25888916doi: 10.1186/s13287-015-0050-0google scholar: lookup
  17. Guest DJ, Smith MR, Allen WR. Equine embryonic stem-like cells and mesenchymal stromal cells have different survival rates and migration patterns following their injection into damaged superficial digital flexor tendon.. Equine Vet J 2010 Oct;42(7):636-42.
    pubmed: 20840579doi: 10.1111/j.2042-3306.2010.00112.xgoogle scholar: lookup
  18. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting.. Blood 2006 Sep 15;108(6):2114-20.
    pmc: PMC1895546pubmed: 16690970doi: 10.1182/blood-2005-11-011650google scholar: lookup
  19. Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral alloimmune response.. Biol Blood Marrow Transplant 2007 Apr;13(4):412-22.
    pmc: PMC1892590pubmed: 17382248doi: 10.1016/j.bbmt.2006.12.447google scholar: lookup
  20. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R, Reisner Y. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells.. Stem Cells 2009 Nov;27(11):2865-74.
    pubmed: 19750539doi: 10.1002/stem.217google scholar: lookup
  21. Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice.. Blood 2005 Dec 15;106(13):4057-65.
    pubmed: 16118325doi: 10.1182/blood-2005-03-1004google scholar: lookup
  22. Adams AP, Antczak DF. Ectopic transplantation of equine invasive trophoblast.. Biol Reprod 2001 Mar;64(3):753-63.
    pubmed: 11207188doi: 10.1095/biolreprod64.3.753google scholar: lookup
  23. Antczak DF, Bright SM, Remick LH, Bauman BE. Lymphocyte alloantigens of the horse. I. Serologic and genetic studies.. Tissue Antigens 1982 Sep;20(3):172-87.
    pubmed: 6182639doi: 10.1111/j.1399-0039.1982.tb00343.xgoogle scholar: lookup
  24. Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, Suberbielle C, Frémeaux-Bacchi V, Méjean A, Desgrandchamps F, Anglicheau D, Nochy D, Charron D, Empana JP, Delahousse M, Legendre C, Glotz D, Hill GS, Zeevi A, Jouven X. Complement-binding anti-HLA antibodies and kidney-allograft survival.. N Engl J Med 2013 Sep 26;369(13):1215-26.
    pubmed: 24066742doi: 10.1056/nejmoa1302506google scholar: lookup
  25. Hirata AA, Terasaki PI. Cross-reactions between streptococcal M proteins and human transplantation antigens.. Science 1970 May 29;168(3935):1095-6.
    pubmed: 4909764doi: 10.1126/science.168.3935.1095google scholar: lookup
  26. Pantenburg B, Heinzel F, Das L, Heeger PS, Valujskikh A. T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection.. J Immunol 2002 Oct 1;169(7):3686-93.
    pubmed: 12244161doi: 10.4049/jimmunol.169.7.3686google scholar: lookup
  27. Amir AL, D'Orsogna LJ, Roelen DL, van Loenen MM, Hagedoorn RS, de Boer R, van der Hoorn MA, Kester MG, Doxiadis II, Falkenburg JH, Claas FH, Heemskerk MH. Allo-HLA reactivity of virus-specific memory T cells is common.. Blood 2010 Apr 15;115(15):3146-57.
    pubmed: 20160165doi: 10.1182/blood-2009-07-234906google scholar: lookup
  28. Spurlock GH, Spurlock SL, Parker GA. Ultrasonographic, gross, and histologic evaluation of a tendonitis disease model in the horse. Vet. Radiol. Ultrasound 30, 184–188.
  29. Haynes MK, Hume EL, Smith JB. Phenotypic characterization of inflammatory cells from osteoarthritic synovium and synovial fluids.. Clin Immunol 2002 Dec;105(3):315-25.
    pubmed: 12498813doi: 10.1006/clim.2002.5283google scholar: lookup
  30. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy.. Circ Res 2008 Nov 21;103(11):1204-19.
    pmc: PMC2667788pubmed: 19028920doi: 10.1161/circresaha.108.176826google scholar: lookup
  31. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells.. Cytokine Growth Factor Rev 2009 Oct-Dec;20(5-6):419-27.
    pubmed: 19926330doi: 10.1016/j.cytogfr.2009.10.002google scholar: lookup

Citations

This article has been cited 46 times.
Subscribe to our newsletter
Join 99,850 horse owners like you who receive our email updates on horse health and nutrition.