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Creating Tolerance for Human Embryonic Stem Cell Graft Derivatives

Review of “Tolerance Induction and Reversal of Diabetes in Mice Transplanted with Human Embryonic-Stem-Cell-Derived Pancreatic Endoderm” from Cell Stem Cell by Stuart P. Atkinson

T cell-mediated destruction of pancreatic insulin-producing cells leads to Type 1 diabetes (T1D) [1], which is usually treated with daily insulin injections often leading to complications and reduced quality of life [2]. Many researchers consider cell replacement therapies as a highly appealing alternative strategy. A lack of donor organs has prompted many to explore human embryonic stem cell (hESC) differentiation to functional cells as a possible alternate route to transplantable cells, and this has met with great success (See original article for extensive references). However, immune rejection is still a potential obstacle, and in a recent study in Cell Stem Cell, researchers from the laboratory of Jeffrey A. Bluestone (Diabetes Center, University of California, San Francisco) have shown that immune-competent mice reject hESC-derived pancreatic endoderm (hESC-PE). However, they go on to show that a co-stimulation blockade regimen mediates immune tolerance and the proper function of hESC-derived cells [3].

Previous studies demonstrated the ability of hESC-PE to give rise to islet-structures after transplant into immune-deficient mice [4], and in this study, the researchers found that functionality of these islets did not change in response to the presence of immune cells of the innate immune system (natural killer cells or innate lymphoid cells).  However, transplantation of cells into immune-competent mice led to rejection and a decrease in graft functionality, suggesting that the adaptive immune system (T and B lymphocytes) may be central to transplant rejection. Blockade of T-cell co-stimulatory pathways blocks graft rejection [5], and hESC-PE transplant alongside co-stimulation-blocking monoclonal antibodies (CTLA4Ig and anti-CD40L mAbs) inhibited rejection and mediated graft function. Furthermore, this immune tolerance was long-lived and transferrable, as the authors observed the tolerance of cells from an animal undergoing co-stimulation blockade after transfer into another animal in the absence of immunosuppression. The authors also went on to show that this tolerance was not affected by the presence or absence of regulatory T cells; previously shown to play a role in the maintenance of tolerance to self-antigens in homeostatic conditions. Finally, Szot et al studied graft tolerance in a humanized mouse model of transplantation, which includes the transfer of healthy human PBMCs with or without co-stimulation blockade (CTLA4Ig + anti-human CD40L mAbs). Encouragingly, grafted cells remained functional and islet cells were not rejected by human PBMCs, but only in the presence of the blockade.

This short-term tolerance treatment has the possibility to enhance the long term success of islet cell replacement in T1D, and perhaps other cell replacement therapies. This may also propel the use of hESCs instead of patient-specific human induced pluripotent stem cells (hiPSCs), and so reducing time and monetary costs and open this therapeutic strategy to a wider audience. Further research will have to assess differing hESCs and differing derivatives, but the importance for this research and preclinical development of therapies still remains.

References

  1. Bluestone JA, Herold K, and Eisenbarth G Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010;464:1293-1300.
  2. Kilpatrick ES, Rigby AS, and Atkin SL The Diabetes Control and Complications Trial: the gift that keeps giving. Nat Rev Endocrinol 2009;5:537-545.
  3. Szot GL, Yadav M, Lang J, et al. Tolerance Induction and Reversal of Diabetes in Mice Transplanted with Human Embryonic-Stem-Cell-Derived Pancreatic Endoderm. Cell Stem Cell 2014;
  4. Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nature biotechnology 2008;26:443-452.
  5. Salomon B and Bluestone JA Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 2001;19:225-252.