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.2 Protection from NK mediated damage

Lorenzo Piemonti, Italy

Diabetes Research Institute and Regenerative Medicine and Transplant Unit
IRCCS Ospedale San Raffaele


Lorenzo Piemonti, MD, graduated with Summa cum Laude at the University of Milan in 1994, and specialized with Summa Cum Laude in Endocrinology and Metabolic Diseases and in Micro and Experimental surgery at the University of Milan in 2000 and 2004, respectively. At the San Raffaele Scientific Institute (Milan, Italy) he serves as Director of Diabetes Research Institute and Head Physician of the Transplant and Regenerative Medicine Unit. He also serves as Professor in Endocrinology at University “Vita Salute San Raffaele” of Milan and as Honorary Visiting Professor at Vrije Universiteit of Brussel. His area of expertise is mainly focused on diabetes and pancreatology. In particular, he has large experience about diabetes therapy and pathophysiology, regenerative medicine and pancreatic cancer. In addition, his research interests include beta cell replacement, immune tolerance induction strategies, dendritic cell biology, and stem cells. He currently serves as section Editor of Cell Transplantation-the Regenerative Medicine Journal, as associated editor of Transplant International and Journal of Endocrinological Investigation, as member of editorial board of Acta Dibetologia, as treasurer of the International Pancreas and Islet Transplantation Association (2019-2023, IPITA) of The Transplantation Society (TTS), as member of the steering committee The European Pancreas and Islet Transplant Registry (EPITR 2020-2025) and as member of the National Board and scientific coordinator of the Italian Society of Diabetes (SID, 2020-2024). He previously served (2011-2017) as member of the European Pancreas and Islet Transplantation Association (EPITA) committee of European Society for Organ Transplantation (ESOT), as member of the National Committee for Food Safety (2018-2021, Italian Ministry of Health),and as Councilor of IPITA (2015-2019). Publication activity (December 2022) Lorenzo Piemonti authored a total of 285 original articles published in peer-reviewed journals surveyed in PubMed. H-index (31/12/2022): 61 Web of Science; 64 Scopus; 73 Google Scholar. Considering the period 2017-present Lorenzo Piemonti authored a total of 122 original articles published in peer-reviewed journals for an impact factor of 902.505 (mean impact factor: 7.398)


Protection from NK mediated damage

Lorenzo Piemonti1,2, Valeria Sordi1.

1Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; 2Department of regenerative and transplant medicne, Università Vita Salute San Raffaele, Milan, Italy

Transplantation of pancreatic islets or β cells has been shown to be a potential cure for T1D, but the shortage of donor organs limits the availability of this therapy. Induced pluripotent stem cells (iPSCs) hold great promise as a source of pancreatic β cells for cell therapy because they can differentiate into virtually any cell type in the body, including β cells. However, the immune response limits the use of autologous cell engraftment, while transplantation of allogeneic iPSC pancreatic derivatives leads to CD8+ T cell-mediated allograft rejection.


To overcome this problem, researchers have explored various strategies to make iPSC-derived cells less visible to the immune system. One strategy involves using MHC-I-/- iPSCs, which lack the major histocompatibility complex class I (MHC-I) molecules that present antigens to CD8+ T cells. However, this strategy may trigger missing-self recognition by natural killer (NK) cells, which can recognize cells that lack MHC-I molecules.


Recent studies have shown that two immune checkpoints, B7-H3 and CD155, are highly expressed in iPSC-derived pancreatic progenitors (iPPs) and function as NK cell activating receptor ligands. Therefore, researchers used CRISPR/Cas9 technology to generate MHC-I-deprived B7H3-/-/CD155-/- iPPs and tested their ability to evade NK response in vivo. The engineered iPPs were transplanted into humanized mice alongside wild-type (WT) and MHC-I-/- iPPs.


The results showed that MHC-I-/-/B7H3-/-/CD155-/- cells evaded immune recognition in vivo, similar to WT cells. The higher survival rate of the engineered cells correlated with improved maturation capacity of the endocrine progenitors, resulting in a significantly higher number of insulin-secreting β cells than the MHC-I-/- iPPs.


This study suggests that NK activating receptor ligands could be used as novel targets to make grafts invisible to immune cell recognition in vivo, offering new possibilities for using clinical-grade iPSC pancreatic derivatives as next-generation cell therapy for T1D treatment. These findings could be significant in enhancing the effectiveness of iPSC-derived cell therapies for T1D and may have implications for the development of cell therapies for other autoimmune diseases as well.


In conclusion, the use of iPSCs as a source of pancreatic β cells for T1D therapy holds great promise, but the immune response limits their effectiveness. The strategy of using MHC-I-/- iPSCs has been explored, but it may trigger NK cell recognition. The present study offers a new approach by using CRISPR/Cas9 technology to generate MHC-I-deprived B7H3-/-/CD155-/- iPPs that evade immune recognition in vivo. This strategy could enhance the effectiveness of iPSC-derived cell therapies for T1D and other autoimmune diseases.

This work was supported by the European Commission (H2020 grant 681070), Fondazione Italiana Diabete Onlus, “I love Riccio” and “Un brutto t1po” fundraising campaigns, and SOStegno 70 Insieme ai ragazzi diabetici Associazione Onlus (Project “Beta is better”).

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