Skip to main content

Advertisement

SpringerLink
Log in

Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection.

Methods

Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice).

Results

In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection.

Conclusion

Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nathan DM, Cleary PA, Backlund JY et al (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653

    Article  PubMed  Google Scholar 

  2. Nathan DM, Lachin J, Cleary P et al (2003) Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 348:2294–2303

    Article  PubMed  Google Scholar 

  3. Bloomgarden ZT (2004) Consequences of diabetes: cardiovascular disease. Diabetes Care 27:1825–1831

    Article  PubMed  Google Scholar 

  4. Bloomgarden ZT (2004) Diabetes complications. Diabetes Care 27:1506–1514

    Article  PubMed  Google Scholar 

  5. Trento M, Raballo M, Trevisan M et al (2012) A cross-sectional survey of depression, anxiety, and cognitive function in patients with type 2 diabetes. Acta Diabetol 49:199–203

    Article  CAS  PubMed  Google Scholar 

  6. Piarulli F, Sartore G, Lapolla A (2013) Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update. Acta Diabetol 50:101–110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Tarallo S, Beltramo E, Berrone E, Porta M (2012) Human pericyte-endothelial cell interactions in co-culture models mimicking the diabetic retinal microvascular environment. Acta Diabetol 49(Suppl 1):S141–S151

    Article  PubMed  Google Scholar 

  8. Fiorina P, Shapiro AM, Ricordi C, Secchi A (2008) The clinical impact of islet transplantation. Am J Transplant 8:1990–1997

    Article  CAS  PubMed  Google Scholar 

  9. Fiorina P, Vergani A, Petrelli A et al (2008) Metabolic and immunological features of the failing islet-transplanted patient. Diabetes Care 31:436–438

    Article  CAS  PubMed  Google Scholar 

  10. Fiorina P, Vezzulli P, Bassi R et al (2012) Near normalization of metabolic and functional features of the central nervous system in type 1 diabetic patients with end-stage renal disease after kidney-pancreas transplantation. Diabetes Care 35:367–374

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Venturini M, Fiorina P, Maffi P et al (2006) Early increase of retinal arterial and venous blood flow velocities at color Doppler imaging in brittle type 1 diabetes after islet transplant alone. Transplantation 81:1274–1277

    Article  PubMed  Google Scholar 

  12. Del Carro U, Fiorina P, Amadio S et al (2007) Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care 30:3063–3069

    Article  PubMed  Google Scholar 

  13. Fiorina P, Secchi A (2007) Pancreatic islet cell transplant for treatment of diabetes. Endocrinol Metab Clin North Am 36:999–1013; ix

  14. Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330

    Article  CAS  PubMed  Google Scholar 

  15. Ansari MJ, Fiorina P, Dada S et al (2008) Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clin Immunol 126:140–147

    Article  CAS  PubMed  Google Scholar 

  16. Guleria I, Gubbels Bupp M, Dada S et al (2007) Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clin Immunol 125:16–25

    Article  CAS  PubMed  Google Scholar 

  17. Vergani A, D’Addio F, Jurewicz M et al (2010) A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice. Diabetes 59:2253–2264

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Vergani A, Fotino C, D’Addio F et al (2013) Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62:1665–1675

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Maffi P, Bertuzzi F, De Taddeo F et al (2007) Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care 30:1150–1155

    Article  CAS  PubMed  Google Scholar 

  20. Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403

    CAS  PubMed  Google Scholar 

  21. Tyndall A, Walker UA, Cope A et al (2007) Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005. Arthritis Res Ther 9:301

    Article  PubMed Central  PubMed  Google Scholar 

  22. Cohen JA (2013) Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci 333:43–49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Fiorina P, Jurewicz M, Augello A et al (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183:993–1004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Fiorina P, Voltarelli J, Zavazava N (2011) Immunological applications of stem cells in type 1 diabetes. Endocr Rev 32:725–754

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Oswald J, Boxberger S, Jorgensen B et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384

    Article  PubMed  Google Scholar 

  26. Le Blanc K, Samuelsson H, Lonnies L, Sundin M, Ringden O (2007) Generation of immunosuppressive mesenchymal stem cells in allogeneic human serum. Transplantation 84:1055–1059

    Article  PubMed  Google Scholar 

  27. De Miguel MP, Fuentes-Julian S, Blazquez-Martinez A et al (2012) Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 12:574–591

    Article  PubMed  Google Scholar 

  28. MacFarlane RJ, Graham SM, Davies PS et al (2013) Anti-inflammatory role and immunomodulation of mesenchymal stem cells in systemic joint diseases: potential for treatment. Expert Opin Ther Targets 17:243–254

    Article  CAS  PubMed  Google Scholar 

  29. Jurewicz M, Yang S, Augello A et al (2010) Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 59:3139–3147

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Papadopoulou A, Yiangou M, Athanasiou E et al (2012) Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis. Ann Rheum Dis 71:1733–1740

    Article  PubMed  Google Scholar 

  31. Eggenhofer E, Renner P, Soeder Y et al (2011) Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transpl Immunol 25:141–147

    Article  CAS  PubMed  Google Scholar 

  32. Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58:1797–1806

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Carvello M, Petrelli A, Vergani A et al (2012) Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses. Diabetes 61:155–165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Serreze DV, Chapman HD, Varnum DS et al (1996) B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J Exp Med 184:2049–2053

    Article  CAS  PubMed  Google Scholar 

  35. Vergani A, Clissi B, Sanvito F, Doglioni C, Fiorina P, Pardi R (2009) Laser capture microdissection as a new tool to assess graft-infiltrating lymphocytes gene profile in islet transplantation. Cell Transplant 18:827–832

    Article  CAS  PubMed  Google Scholar 

  36. Vergani A, Tezza S, D’Addio F et al (2013) Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127:463–475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Astorri E, Fiorina P, Gavaruzzi G, Astorri A, Magnati G (1997) Left ventricular function in insulin-dependent and in non-insulin-dependent diabetic patients: radionuclide assessment. Cardiology 88:152–155

    Article  CAS  PubMed  Google Scholar 

  38. Paroni R, Fermo I, Fiorina P, Cighetti G (2005) Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects. Amino Acids 28:389–394

    Article  CAS  PubMed  Google Scholar 

  39. Fiorina P, Vergani A, Dada S et al (2008) Targeting CD22 reprograms B-cells and reverses autoimmune diabetes. Diabetes 57:3013–3024

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Francese R, Fiorina P (2010) Immunological and regenerative properties of cord blood stem cells. Clin Immunol 136:309–322

    Article  CAS  PubMed  Google Scholar 

  41. D’Addio F, Maffi P, Vezzulli P et al (2014) Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes. Diabetes Care 37:267–276

    Article  PubMed Central  PubMed  Google Scholar 

  42. Gu F, Molano I, Ruiz P, Sun L, Gilkeson GS (2012) Differential effect of allogeneic versus syngeneic mesenchymal stem cell transplantation in MRL/lpr and (NZB/NZW)F1 mice. Clin Immunol 145:142–152

    Article  CAS  PubMed  Google Scholar 

  43. Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J (2005) Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 106:4057–4065

    Article  CAS  PubMed  Google Scholar 

  44. Ito T, Itakura S, Todorov I et al (2010) Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation 89:1438–1445

    Article  PubMed  Google Scholar 

  45. Borg DJ, Weigelt M, Wilhelm C et al (2014) Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Diabetologia 57:522–531

    Article  PubMed  Google Scholar 

  46. Rossignol J, Boyer C, Leveque X et al (2011) Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington’s disease: morphological and behavioral outcomes. Behav Brain Res 217:369–378

    Article  CAS  PubMed  Google Scholar 

  47. Park KS, Kim YS, Kim JH et al (2010) Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation 89:509–517

    CAS  PubMed  Google Scholar 

  48. Favaro E, Carpanetto A, Lamorte S et al (2014) Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia 57:1664–1673

    Article  CAS  PubMed  Google Scholar 

  49. Cantaluppi V, Biancone L, Figliolini F et al (2012) Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant 21:1305–1320

    Article  PubMed  Google Scholar 

  50. Yagi H, Soto-Gutierrez A, Parekkadan B et al (2010) Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant 19:667–679

    Article  PubMed Central  PubMed  Google Scholar 

  51. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827

    Article  CAS  PubMed  Google Scholar 

  52. Jiang XX, Zhang Y, Liu B et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126

    Article  CAS  PubMed  Google Scholar 

  53. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (2006) 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 107:1484–1490

    Article  CAS  PubMed  Google Scholar 

  54. Corcione A, Benvenuto F, Ferretti E et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372

    Article  CAS  PubMed  Google Scholar 

  55. Duprez IR, Johansson U, Nilsson B, Korsgren O, Magnusson PU (2011) Preparatory studies of composite mesenchymal stem cell islets for application in intraportal islet transplantation. Ups J Med Sci 116:8–17

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Paolo Fiorina is the recipient of a JDRF Career Development Award, an ASN Career Development Award, and an ADA Mentor-based Fellowship Grant. P.F. is also supported by a Translational Research Program (TRP) Grant from Boston Children’s Hospital; Harvard Stem Cell Institute Grant (“Diabetes Program” DP-0123-12-00); Italian Ministry of Health Grant RF- 2010-2303119. P. F. and Andrea Vergani are supported of an Italian Ministry of Health Grant: (“Staminali” RF-FSR-2008-1213704). A.V. is supported by the “AMD-SID Pasquale di Coste Scolarship”. Francesca D’Addio is a recipient of Italian Scientists and Scholars of North America Foundation (ISSNAF)-Fondazione Marche Fellowship. Roberto Bassi is supported by an ADA Mentor-based Fellowship Grant to P.F and by an AST Genentech Clinical Science Fellowship Grant. A.V. conducted this study as partial fulfillment of his PhD in Molecular Medicine, San Raffaele University, Milan, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

Principles of laboratory animal care” (NIH publication No. 86-23, revised 1985) were followed, as well as specific national laws (e.g., the current version of the German Law on the Protection of Animals) were applicable.

Informed consent

This study does not involve human subjects. No informed consent needs to be obtained.

Author information

Author notes

    Authors and Affiliations

    1. Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Enders Building 5th Floor Room EN511, 300 Longwood Ave, Boston, MA, USA

      Moufida Ben Nasr, Andrea Vergani, Francesca D’Addio, Sara Tezza, Roberto Bassi & Paolo Fiorina

    2. Transplant Medicine, Ospedale San Raffaele, Milan, Italy

      Moufida Ben Nasr, Andrea Vergani, Francesca D’Addio, Alessandro Valderrama-Vasquez, Vera Usuelli & Paolo Fiorina

    3. Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

      James Avruch, Liye Liu, James Kim & James Markmann

    4. Renal Division, Brigham and Women’s Hospital, Harvard Institute of Medicine, HIM510, Harvard Medical School, Boston, MA, 02115, USA

      Eirini Kefaloyianni

    5. Pathology and Laboratory Medicine, University of Parma, Parma, Italy

      Domenico Corradi

    6. Nephrology Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

      Jamil Azzi & Reza Abdi

    7. Department of Medicine, Al-Azhar University, Cairo, Egypt

      Basset El Essawy

    Authors
    1. Moufida Ben Nasr
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Andrea Vergani
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. James Avruch
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Liye Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Eirini Kefaloyianni
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Francesca D’Addio
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Sara Tezza
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Domenico Corradi
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Roberto Bassi
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Alessandro Valderrama-Vasquez
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Vera Usuelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. James Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Jamil Azzi
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Basset El Essawy
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. James Markmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Reza Abdi
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Paolo Fiorina
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Paolo Fiorina.

    Additional information

    Managed by Massimo Federici.

    Moufida Ben Nasr and Andrea Vergani have contributed equally to the paper.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ben Nasr, M., Vergani, A., Avruch, J. et al. Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site. Acta Diabetol 52, 917–927 (2015). https://doi.org/10.1007/s00592-015-0735-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00592-015-0735-y

    Keywords

    Search

    Navigation