Experimental Hematology
Volume 38, Issue 10 , Pages 957-967.e1 , October 2010

Cell-dose−dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs

  • Iryna A. Isakova

      Affiliations

    • Department of Surgery, Tulane Medical School, New Orleans, La., USA
  • ,
  • Jason Dufour

      Affiliations

    • Department of Veterinary Medicine, Tulane National Research Primate Center, Covington, La., USA
  • ,
  • Calvin Lanclos

      Affiliations

    • Department of Immunology, Tulane National Research Primate Center, Covington, La., USA
  • ,
  • Julie Bruhn

      Affiliations

    • Department of Immunology, Tulane National Research Primate Center, Covington, La., USA
  • ,
  • Donald G. Phinney

      Affiliations

    • Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Fla., USA
    • Corresponding Author InformationOffprint requests to: Donald G. Phinney, Ph.D., Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, A213, Jupiter, FL 33458

Received 3 May 2010 ,Revised 16 June 2010 ,Accepted 28 June 2010.

References 

  1. Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36:2566–2573
  2. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft in vivo. Exp Hematol. 2002;30:42–48
  3. Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102:3837–3844
  4. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005;106:1755–1761
  5. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–1586
  6. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843
  7. Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res. 2005;305:33–41
  8. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune responses. Blood. 2005;105:1815–1822
  9. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone-marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103:4619–4621
  10. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immuno-suppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150
  11. 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;106:4057–4065
  12. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EGA, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a non-myeloablative setting. Blood. 2006;108:2114–2120
  13. Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral immune response. Biol Blood Marrow Transplant. 2007;13:412–422
  14. Poncelet AJ, Vercruysse J, Saliez A, Gianello P. Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo. Transplantation. 2007;83:783–790
  15. Sudres M, Norol F, Trenado A, et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol. 2006;176:7761–7767
  16. Ankrum J, Karp JM. Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol Med. 2010;16:203–209
  17. Mestas J, Hughes CC. Of mice and men: differences between mouse and human immunology. J Immunol. 2004;172:2731–2738
  18. Isakova IA, Phinney DG. Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Curr Pharm Des. 2005;11:1255–1265
  19. Cserr HF, Harling-Berg CJ, Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992;2:269–276
  20. Hickey WF. Basic principles of immunological surveillance of the normal central nervous system. Glia. 2001;36:118–124
  21. Stonestreet BS, Patlak CS, Pettigrew KD, Reilly CB, Cserr HF. Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults. Am J Physiol. 1996;271:1594–1601
  22. Engelhardt B. The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des. 2008;14:1555–1565
  23. Phillips LM, Lampson LA. Site-specific control of T cell traffic in the brain: T cell entry to brainstem vs. hippocampus after local injection of IFN-gamma. J Neuroimmunol. 1999;96:218–227
  24. Becher B, Prat A, Antel JP. Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia. 2000;29:293–304
  25. Rock RB, Gekker G, Hu S, et al. Role of microglia in central nervous system infections. Clin Microbiol Rev. 2004;17:942–964
  26. Isakova IA, Baker K, Dufour J, Gaupp D, Phinney DG. Preclinical evaluation of adult stem cell engraftment and toxicity in the CNS of rhesus macaques. Mol Ther. 2006;13:1173–1184
  27. Isakova IA, Baker K, Dutreil M, Dufour J, Gaupp D, Phinney DG. Age- and dose-related effects on MSC engraftment levels and anatomical distribution in the central nervous systems of nonhuman primates: identification of novel MSC subpopulations that respond to guidance cues in brain. Stem Cells. 2007;25:3261–3270
  28. Kaizu M, Borchardt GJ, Glidden CE, et al. Molecular typing of major histocompatibility complex class I alleles in the Indian rhesus macaque which restrict SIV CD8+ T cell epitopes. Immunogenetics. 2007;59:693–703
  29. Fortman JD, Hewett TA, Bennett BT. The laboratory nonhuman primate. Boca Raton, FL: CRC Press; 2002;
  30. Doxiadis , Smits JM, Schreuder GM, et al. Association between specific HLA combinations and probability of kidney allograft loss: the taboo concept. Lancet. 1996;348:850–853
  31. Claas FH, Dankers MK, Oudshoorn M, et al. Differential immunogenicity of HLA mismatches in clinical transplantation. Transplant Immunol. 2005;14:187–191
  32. Rasmusson I, Uhlin M, Le Blanc K, Levitsky V. Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes. J Leukoc Biol. 2007;82:887–893
  33. Devine SM, Bartholomew AM, Mahmud N, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol. 2001;29:244–255
  34. Beggs KJ, Lyubimov A, Borneman JN, et al. Immunological consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons. Cell Transplant. 2006;15:711–721
  35. Cabellero A, Fernandez N, Lavado R, Bravo MJ, Miranda JM, Alonso A. Tolerogenic response: allorecognition pathways. Transplant Immunol. 2006;17:3–6
  36. Whitelegg A, Barber LD. The structural basis of T-cell allorecognition. Tissue Antigens. 2004;63:101–108
  37. Sherman LA, Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol. 1993;11:385–402
  38. Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol. 2001;166:973–981
  39. Gudmundsdottir H, Turka LA. T-cell costimulatory blockade: new therapies for transplant rejection. J Am Soc Nephrol. 1999;10:1356–1365
  40. Sundin M, Barrett JA, Ringden O, et al. HSCT recipients have specific tolerance to MSC but not the MSC donor. J Immunother. 2009;32:755–764
  41. Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci. 2005;12:47–57
  42. Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood. 2003;101:2999–3001
  43. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;230:225–274
  44. Bix M, Liao N-S, Zijlstra M, Loring J, Jaenisch R, Raulet D. Rejection of class I MHC deficient hematopoietic cells by irradiated MHC-mismatched mice. Nature. 1991;349:329–331
  45. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta I. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2 induced NK-cell proliferation. Blood. 2006;107:1484–1490
  46. Lanier LL, Kipps TJ, Phillips JH. Functional properties of a unique subset of cytotoxic CD3+ T lymphocytes that express Fc receptors for IgG (CD16/Leu-11 antigen). J Exp Med. 1985;162:2089–2106
  47. Bjorkstrom N, Gonzalez V, Malmberg K-J, et al. Elevated numbers of FcγRIIIA+ (CD16+) effector CD8 T cells with NK cell-like function in chronic hepatitis C virus infection. J Immunol. 2008;181:4219–4228
  48. Rutjens E, Mazza S, Biassoni R, et al. CD8(+) NK cells are predominant in chimpanzees and characterized by high NCR expression and cytokine production and preserved in chronic HIV-1 infection. Eur J Immunol. 2010;40:1440–1450

PII: S0301-472X(10)00267-5

doi: 10.1016/j.exphem.2010.06.011

Experimental Hematology
Volume 38, Issue 10 , Pages 957-967.e1 , October 2010