Stems Cells and Immunity

Since the early days of modern medicine it has been known that transplantation of tissues from one individual to other results in immune rejection, except when performed between identical twins. Extensive research done in the past decades has uncovered that differences in protein sequences between individuals are the primary targets for the immune response against allogeneic (genetically non-identical) grafts. These molecules were subsequently defined as histocompatibility antigens as they determine whether implanted cells are accepted or rejected by the immune system. Today, the risk of organ rejection remains high despite efforts to match haplotypes of histocompatibility antigens as well as use of immunosuppressive therapies.

Human embryonic stem cells (hESCs) can be propagated in high numbers in vitro, and have the potential to differentiate into a myriad of cell the application of these cells for organ restoration is of particular importance due to limited availability of donated organs. However, it is unclear whether differentiated hESCs will be recognized by the immune system following implantation in humans. Therefore it is imperative to investigate the immune response against differentiated hESCs for successful clinical translation.

The purpose of this review is to describe the current knowledge of antigenicity and immunogenicity of hESCs and their derivatives. While antigenicity refers only to the capacity of cells to express histocompatibility antigens, immunogenicity is a broader term for the potential to elicit immune response through additional factors, such as co-stimulatory molecules. This review summarizes our current view of the histocompatibility antigens and immunomodulating molecules that are expressed on undifferentiated and differentiated hESCs (u/dhESCs). In addition, adaptive and innate immune processes that may develop against the cells following recognition of histocompatibility antigens will be discussed. As rejection processes could severely limit the use of hESC-derived transplants, multiple approaches are being developed to alleviate these risks. I will focus on techniques for derivation of isogenic (genetically identical) hESC lines and discuss the immunological benefits and remaining challenges for their potential application.

·               Expression of histocompatibility antigens on u/dhESCs

·               Expression of T-cell regulating signals in u/dhESCs

·               T-cell response against u/dhESCs measured by functional assays

·               Generation of patient-specific isogenic hESC lines

·               Evidence that malignant progenitor cells

·               Donor natural killer (NK) cells as mediators

·               Antigen processing and presentation

·               Nucleic Acid Sensing Pathways

  • Donor Natural Killer (NK) Cells
  • Immunogenetics

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