Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection

Abstract

Highlights d Deletion of individual HLA genes protects b cells from T-cellmediated rejection d Genome editing of stem cells does not affect their b cell differentiation potential d Retention of HLA-A2 promotes surface expression of HLA-E and reduces NK cell activity d HLA-A2 retention reduces rejection while allowing immune surveillance of the graft

Modeling human T1D-associated autoimmune processes

“…Using NSG mice as the recipient greatly improved PBMC engraftment but the mice rapidly developed an acute xGvHD, accelerated with low-dose irradiation [ 109 ]. Confirming the hypothesis that lethal xGvHD was directed against the murine MHC class I and class II molecules, human PBMCs engrafted into MHC class I/II-deficient NSG mice did not induce acute xGvHD [ 90 , 114 , 136 ] and the engrafted T cells retained their function and were able to reject primary and stem cell-derived islet allografts [ 90 , 114 ]. However, the development of acute xGvHD, even in the absence of murine MHC class I and class II molecules, occurs upon the administration of high levels of human IL-2, which indicates that murine MHC class I and II are not the only molecules controlling the reactivity of xenogeneic human T cells [ 114 ].…”

“…Using multiple isogenic cell types ensures that the interactions observed are devoid of confounding background such as allogeneic reactivity. When the use of primary T cells is needed, it is possible to use autologous cells (from the iPSC donor) or to selectively remove specific HLA molecules in order to prevent alloreactivity while retaining the HLA/peptide–TCR interaction of interest [ [88] , [89] , [90] ]. The possibility of using primary T cells is particularly important, as the differentiation of T cells from iPSCs is not yet possible until these T cells can undergo selection in the presence of TECs.…”

Emerging diabetes therapies: Bringing back the β-cells

“…Using genomic engineering [ [44] , [45] , [46] , [47] ] or epigenetic modification [ 20 ], several groups have reported the successful generation of hypoimmune PSCs and cells derived therefrom [ 42 ]. These “immune cloaking” strategies usually work either by removing receptors important for immune cell recognition or by artificially elevating immune suppressive protein (e.g., immune checkpoint inhibitors) levels on the surface of the cells.…”

Preclinical Models to Evaluate the Human Response to Autoantigen and Antigen-Specific Immunotherapy in Human Type 1 Diabetes

“…Another NSG mouse model was created by transferring genetically modified human embryonic stem cells that lacked CIITA and expressed HLA-A2 as the only HLA class-I molecule. The differentiation of these cells into β-cells then the engraftment with human PBMCs allowed to study the immune response and the islet rejection ( 97 ). Genetically modified β-cells engraftment is another promising therapy to prevent T1D recurrence post engraftment; human β-cells engineered to express Herpesvirus encoded immune-evasion proteins prevent islet destruction in NSG mice by degrading MHC class-I molecules and inhibiting granzyme B activity ( 98 ).…”