BACK TO THE FUTURE – Unveiling the Immunomodulatory Properties of Antigen Presenting Cells

CellR4 2013; 1 (3): e643

  Category:

Abstract

Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplantation Science 1992; 2: 34-38.Article

The full text of the manuscript is available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092700/

Remarkable progress of the past four decades in organ recovery, preservation and transplantation techniques, as well as in the management of immune therapy have allowed achieving reproducibly long-term survival of transplanted tissues. However, chronic immunosuppression remains one of the major challenges of organ transplantation due to the untowards side effects such as organ toxicity, increased risk of opportunistic infections and neoplasms. Multiple strategies are being evaluated to induce immune tolerance to transplanted tissues and promote long-lasting graft function, while avoiding the burden of anti-rejection therapy in transplant recipients. In fact, immune tolerance has been considered the Holy Grail of transplant immunobiology.

The clinical feasibility of achieving indefinite acceptance of transplanted organs after discontinuation of anti-rejection drugs originally comes from the observation that several patients who mantained graft survival after weaning chronic immunosuppression for a number of reasons (that is, not necessarily by protocol design). The seminal discovery that the ‘tolerant’ organ transplant recipients displayed persistance of donor mononuclear cells migrating from the transplanted organ(s) to the hosts’ tissues (a phenomenon defined as ‘microchimerism’) 1 , 2 , 3 , 4 prompted exciting research endeavors that led the discovery of the importance of donor dendritic cell (DC) chimerism on graft outcome 5 , 6 , 7 , 8, and to subsequent clinical trials with high doses of donor-specific hematopoietic stem cell inocula (i.e., obtained from vertebral body marrow) 9 , 10 to enhance solid and cellular transplantation outcomes in the last two decades 11 , 12 , 13 , 14 , 15 , 16 , 17, 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27. Only recently, long term acceptance of allogenic solid organ transplantation has been reported in the clinical setting following lympho-ablative protocols combined with donor hematopoietic cell transplantation to induce chimerism and weaning of immunosuppression by design in small cohorts of patients 28 , 29 , 30 , 31 , 32 , 33 , 34. Development of predictive molecular and functional markers 35 , 36 , 37, 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 may assist in discriminating between responders and nonresponders to therapies aimed at promoting immune tolerance allowing for higher degrees of success more reproducibly in future clinical trials.

We feature in the ‘Back to the Future’ section of the current issue of CellR4 a manuscript entitled “Induction of Pancreatic Islet Graft Acceptance: The Role of Antigen Presenting Cells” by Camillo Ricordi, Suzanne T. Ildstad and Thomas E. Starzl published in Transplantation Science 1992 in which it was proposed that Antigen Presenting Cells (APC) may exert immunomodulatory functions able to promote immune tolerance in the context of organ transplantation 46. The full text of the manuscript is available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092700/.

In hindsight, contextualized in the historical timeframe, the working hypothesis of a ‘tolerogenic’ DC had to be considered quite unconventional when it was put forth. Indeed, the putative function of DC was considered to be pro-inflammatory APC in the early 1990’s 47 , 48, and therefore interventions aimed at modulating the immune system to promote self-tolerance (in the case of autoimmunity) and donor-specific transplant tolerance (in the case of cellular or solid organ grafts) were rather focused on their deletion 49 , 50 , 51.

The idea that APC could play an active role in the promotion of immune tolerance stemmed from the original observation by the Authors that donor DC repopulation of the host’s bone marrow was associated with the induction of operational tolerance in full chimeric animals receiving islet xenografts without the need for chronic immunosuppression 52 , 53 , 54 , 55. Thus, they recognized a potential dual role of APC in the context of allograft and xenograft rejection and/or tolerance induction, suggesting the novel concept that “APCs may play an active role in graft acceptance” 56.

Fast-forward to the present time, the scientific community by and large has widely accepted that tolerogenic APC play a critical role in maintaining the homeostasis of the immune system. In recent years, significant research endeavors helped dissecting out the fascinating role of tolerogenic APC and the associated complex immune network interactions, while also exploring strategies aimed at harnessing these properties to promote regulatory immune circuits in the context of autoimmunity, allergy and transplantation 57 , 58 administered under a non-myeolblative low-intensity conditioning protocol 59 , 60. In light of the encouraging results of these clinical trials, it was appropriate to select the manuscript by Drs. Ricordi, Ildstad and Starzl 61 for this issue’s “Back to the Future”, since the initial observations and innovative concept proposed in their manuscript may sound prophetic today, having paved the way for the steady progress of cellular-based therapies to induce transplant tolerance in the clinical arena.

References

  1. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339(8809): 1579-1582.  (back)
  2. Starzl TE, Demetris AJ, Trucco M, Ramos H, Zeevi A, Rudert WA, et al. Systemic chimerism in human female recipients of male livers. Lancet 1992; 340(8824): 876-877.  (back)
  3. Starzl TE, Demetris AJ, Murase N, Thomson AW, Trucco M, Ricordi C. Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation. Immunol Today 1993; 14(6): 326-332.  (back)
  4. Starzl TE, Demetris AJ, Trucco M, Ricordi C, Ildstad S, Terasaki PI, et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher’s disease. New Engl J Med 1993; 328(11): 745-749.  (back)
  5. Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplant Sci 1992; 2(1): 34-38.  (back)
  6. Ricordi C, Ildstad ST, Demetris AJ, Abou el-Ezz AY, Murase N, Starzl TE. Donor dendritic cell repopulation in recipients after rat-to-mouse bone-marrow transplantation. Lancet 1992; 339(8809): 1610-1611.  (back)
  7. Ricordi C, Zeng Y, Carroll PB, Rilo HL, Beretier DR, Starzl TE, et al. Islet xenografts in fully xenogeneic (rat—-mouse) chimeras: evidence for normal regulation of function in a xenogeneic mouse environment. Surgery 1992; 112(2): 327-332.  (back)
  8. Zeng YJ, Ricordi C, Tzakis A, Rilo HL, Carroll PB, Starzl TE, et al. Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (WF rat—-B10 mouse). Transplantation 1992; 53(2): 277-283.  (back)
  9. Rybka WB, Fontes PA, Rao AS, Winkelstein A, Ricordi C, Ball ED, et al. Hematopoietic progenitor cell content of vertebral body marrow used for combined solid organ and bone marrow transplantation. Transplantation 1995; 59(6): 871-874.  (back)
  10. Linetsky E, Pileggi A, Khan A, Alejandro R, Inverardi L, Ricordi C. Human Vertebral Body Marrow Processing: Standard Operating Procedure from the cGMP Human Cell Processing Facility of the Cell Transplant Center and Diabetes Research Institute at the University of Miami. CellR4 2013; 1(3): e557.  (back)
  11. Fontes P, Rao AS, Demetris AJ, Zeevi A, Trucco M, Carroll P, et al. Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation. Lancet 1994; 344(8916): 151-155.  (back)
  12. Garcia-Morales R, Esquenazi V, Zucker K, Gomez CI, Fuller L, Carreno M, et al. An assessment of the effects of cadaver donor bone marrow on kidney allograft recipient blood cell chimerism by a novel technique combining PCR and flow cytometry. Transplantation 1996; 62(8): 1149-1160.) , ((Garcia-Morales R, Carreno M, Mathew J, Zucker K, Cirocco R, Ciancio G, et al. The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients. J Clin Invest 1997; 99(5): 1118-1129.  (back)
  13. Tsaroucha AK, Ricordi C, Noto TA, Kenyon NS, Garcia-Morales R, Nery JR, et al. Donor peripheral blood stem cell infusions in recipients of living-related liver allografts. Transplantation 1997; 64(2): 362-364.  (back)
  14. Fontes P, Rogers J, Rao AS, Trucco M, Zeevi A, Ricordi C, et al. Evidence for engraftment of human bone marrow cells in non-lethally irradiated baboons. Transplantation 1997; 64(11): 1595-1598.  (back)
  15. Corry RJ, Chakrabarti PK, Shapiro R, Rao AS, Dvorchik I, Jordan ML, et al. Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients. Ann Surg 1999; 230(3): 372-379; discussion 9-81.  (back)
  16. Pham SM, Rao AS, Zeevi A, Kormos RL, McCurry KR, Hattler BG, et al. A clinical trial combining donor bone marrow infusion and heart transplantation: intermediate-term results. J Thorac Cardiovasc Surg 2000; 119(4 Pt 1): 673-681.  (back)
  17. Mathew JM, Garcia-Morales R, Fuller L, Rosen A, Ciancio G, Burke GW, et al. Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses. Transplantation 2000; 70(12): 1675-1682.  (back)
  18. Pham SM, Rao AS, Zeevi A, McCurry KR, Keenan RJ, Vega JD, et al. Effects of donor bone marrow infusion in clinical lung transplantation. Ann Thorac Surg 2000; 69(2): 345-350.  (back)
  19. Ciancio G, Miller J, Garcia-Morales RO, Carreno M, Burke GW, 3rd, Roth D, et al. Six-year clinical effect of donor bone marrow infusions in renal transplant patients. Transplantation 2001; 71(7): 827-835.  (back)
  20. Ciancio G, Burke GW, Garcia-Morales R, Suzart K, Rosen A, Ricordi C, et al. Effect of living-related donor bone marrow infusion on chimerism and in vitro immunoregulatory activity in kidney transplant recipients. Transplantation 2002; 74(4): 488-496.  (back)
  21. Cirocco RE, Carreno MR, Mathew JM, Garcia-Morales RO, Fuller L, Esquenazi V, et al. FoxP3 mRNA transcripts and regulatory cells in renal transplant recipients 10 years after donor marrow infusion. Transplantation 2007; 83(12): 1611-1619.  (back)
  22. Mineo D, Ricordi C, Xu X, Pileggi A, Garcia-Morales R, Khan A, et al. Combined islet and hematopoietic stem cell allotransplantation: a clinical pilot trial to induce chimerism and graft tolerance. Am J Transplant 2008; 8(6): 1262-1274.  (back)
  23. Mineo D, Ricordi C. Chimerism and liver transplant tolerance. J Hepatol 2008; 49(3): 478-480.  (back)
  24. Fotino C, Ricordi C, Lauriola V, Alejandro R, Pileggi A. Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes. Rev Diabet Studies 2010; 7(2): 144-157.  (back)
  25. Schneeberger S, Gorantla VS, Brandacher G, Zeevi A, Demetris AJ, Lunz JG, et al. Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg 2013; 257(2): 345-351.  (back)
  26. Trivedi HL, Vanikar AV. Mesenchymal Stem Cells And Solid Organ Transplantation. CellR4 2013; 1 (2): e377.  (back)
  27. Trivedi HL, A.V. V, Kute VB, Patel HV, Gumber MR, Shah PR, et al. Pretransplant Infusion of Donor Stem Cells Open Gateway to Tolerance through Induction of Regulatory T Cells and Activation of Other Allosuppressive Immune Mechanisms – Single Centre Experience in Living Donor Renal Transplantation. CellR4 2013; 1(3): e528.  (back)
  28. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. New Engl J Med 2008; 358(4): 353-361.  (back)
  29. Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. New Engl J Med 2008; 358(4): 362-368.  (back)
  30. Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. New Engl J Med 2011; 365(14): 1359-1360.  (back)
  31. Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Sarwal M, Millan MT, et al. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant 2012; 12(5): 1133-1145.  (back)
  32. Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 2012; 4(124): 124ra28.  (back)
  33. Leventhal J, Abecassis M, Miller J, Gallon L, Tollerud D, Elliott MJ, et al. Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome. Transplantation 2013; 95(1): 169-176.  (back)
  34. Kawai T, Sachs DH, Sykes M, Cosimi AB. HLA-mismatched renal transplantation without maintenance immunosuppression. New Engl J Med 2013; 368(19): 1850-1852.  (back)
  35. Baeten D, Louis S, Braud C, Braudeau C, Ballet C, Moizant F, et al. Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients. J Am Soc Nephrol 2006; 17(1): 294-304.  (back)
  36. Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, et al. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant 2007; 7(2): 309-319.  (back)
  37. Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A 2007; 104(39): 15448-15453.  (back)
  38. Braud C, Baeten D, Giral M, Pallier A, Ashton-Chess J, Braudeau C, et al. Immunosuppressive drug-free operational immune tolerance in human kidney transplant recipients: Part I. Blood gene expression statistical analysis. Journal of cellular biochemistry. 2008;103(6):1681-92. Epub 2007/10/03.  (back)
  39. Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest 2010; 120(6): 1848-1861.  (back)
  40. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Investig 2010; 120(6): 1836-1847.  (back)
  41. Hernandez-Fuentes MP, Lechler RI. A ‘biomarker signature’ for tolerance in transplantation. Nature Rev Nephrol 2010; 6(10): 606-613.  (back)
  42. Haynes LD, Jankowska-Gan E, Sheka A, Keller MR, Hernandez-Fuentes MP, Lechler RI, et al. Donor-specific indirect pathway analysis reveals a B-cell-independent signature which reflects outcomes in kidney transplant recipients. Am J Transplant 2012; 12(3): 640-648.  (back)
  43. Braza F, Soulillou JP, Brouard S. Gene expression signature in transplantation tolerance. Clin Chim Acta 2012; 413(17-18): 1414-1418.  (back)
  44. Braza F, Soulillou JP, Brouard S. Reconsidering the bio-detection of tolerance in renal transplantation. Chimerism 2013; 4(1): 15-17.  (back)
  45. Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Suthanthiran M, Tambur A, et al. Genomic biomarkers correlate with HLA-identical renal transplant tolerance. J Am Soc Nephrol 2013; 24(9): 1376-1385.  (back)
  46. Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplant Sci 1992; 2(1): 34-38.  (back)
  47. Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sciences U S A 1978; 75(10): 5132-5136.  (back)
  48. Setum CM, Hegre OD, Serie JR, Moore WV. The potency of splenic dendritic cells as alloantigen presenters in vivo. Quantitation of the number of cells required to achieve graft rejection. Transplantation 1990; 49(6): 1175-1177.  (back)
  49. Lafferty KJ, Cooley MA, Woolnough J, Walker KZ. Thyroid allograft immunogenicity is reduced after a period in organ culture. Science 1975; 188(4185): 259-261.  (back)
  50. Lafferty KJ, Bootes A, Dart G, Talmage DW. Effect of organ culture on the survival of thyroid allografts in mice. Transplantation 1976; 22(2): 138-149.  (back)
  51. Faustman D, Hauptfeld V, Lacy P, Davie J. Prolongation of murine islet allograft survival by pretreatment of islets with antibody directed to Ia determinants. Proc Natl Acad Sciences U S A 1981; 78(8): 5156-5159.  (back)
  52. Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplant Sci 1992; 2(1): 34-38.  (back)
  53. Ricordi C, Ildstad ST, Demetris AJ, Abou el-Ezz AY, Murase N, Starzl TE. Donor dendritic cell repopulation in recipients after rat-to-mouse bone-marrow transplantation. Lancet 1992; 339(8809): 1610-1611.  (back)
  54. Ricordi C, Zeng Y, Carroll PB, Rilo HL, Beretier DR, Starzl TE, et al. Islet xenografts in fully xenogeneic (rat—-mouse) chimeras: evidence for normal regulation of function in a xenogeneic mouse environment. Surgery 1992; 112(2): 327-332.  (back)
  55. Zeng YJ, Ricordi C, Tzakis A, Rilo HL, Carroll PB, Starzl TE, et al. Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (WF rat—-B10 mouse). Transplantation 1992; 53(2): 277-283.  (back)
  56. Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplant Sci 1992; 2(1): 34-38.  (back)
  57. Fugier-Vivier IJ, Rezzoug F, Huang Y, Graul-Layman AJ, Schanie CL, Xu H, et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J Exp Med 2005; 201(3): 373-383.  (back)
  58. Kaufman CL, Colson YL, Wren SM, Watkins S, Simmons RL, Ildstad ST. Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells. Blood 1994; 84(8): 2436-2446.  (back)
  59. Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 2012; 4(124): 124ra28.  (back)
  60. Leventhal J, Abecassis M, Miller J, Gallon L, Tollerud D, Elliott MJ, et al. Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome. Transplantation 2013; 95(1): 169-176.  (back)
  61. Ricordi C, Ildstad ST, Starzl TE. Induction of pancreatic islet graft acceptance: the role of antigen presenting cells. Transplant Sci 1992; 2(1): 34-38.  (back)

To cite this article

BACK TO THE FUTURE – Unveiling the Immunomodulatory Properties of Antigen Presenting Cells

CellR4 2013; 1 (3): e643

Publication History

Published online: 02 Dec 2013