Generating low immunogenic pig pancreatic islet cell clusters for xenotransplantation

Abstract

Diabetes mellitus is characterized by chronic hyperglycaemia caused by abnormalities in insulin secretion, action or both. Eighty to 90% of the cases of diabetes in children and adolescents are suffering from type 1 diabetes resulting from complete autoimmune destruction of pancreatic β-cells through cellular immune responses. [1][2][3] Human allogeneic pancreas transplantation represents a successful treatment of type 1 diabetes.Nevertheless, because of its complexity and the risks associated, such as formation of blood clots, resurgence of pancreatitis and undesired side-effects from the immunosuppressive treatments, it is not considered as routine therapy. 4,5 Human allogeneic transplantation of encapsulated islets has

Current status of xenotransplantation research and the strategies for preventing xenograft rejection

“…Different drugs targeting these costimulatory pathways could be administrated in xenotransplantation, as for example anti-CD40 mAb and CTLA4Ig, as discussed below. In addition, abrogation of SLA-I expression has been proved to silence T-cell and NK cell-mediated cell lysis ( 113 , 114 ).…”

Genetic Modification of Limbal Stem Cells to Decrease Allogeneic Immune Responses

“…Reduction of HLA class I and class II expression in an allotransplantation setting may support graft survival as it was already shown in different models (22,57,58). In the case of corneal transplantation or LSCs transplantation, systemic immunosuppression is used specially in high-risk patients.…”

Immunogenetics of xenotransplantation

“…Therefore, the overexpression of specific genes such as Fas ligand, CTLA4‐Ig, human inhibitory ligand PD‐L1 and anti‐CD2 monoclonal antibodies into the pig source aiming at reducing cellular immune responses towards the reduction of immunosuppression have shown promising results (Bahr et al., 2016; Buermann et al., 2018; Nottle et al., 2017; Tsuyuki et al., 2002; Vabres et al., 2014). In addition, porcine cells with reduced levels of MHC class I or class II expression by silencing β2‐microglobulin (B2M) or MHC class II transactivator (CIITA), respectively, demonstrated to induce significant diminished T‐cell cytotoxicity (Carvalho Oliveira et al., 2020). A combination of different strategies targeting specific molecules may be able to effectively control cell‐mediated rejection of xenotransplants, bringing us one step closer to fulfil the organs demand all over the world.…”

“…Isolated cells were genetically engineered using lentiviral vectors encoding for shRNAs targeting B2M and CIITA transcripts to silence SLA class I and II respectively. SLA‐silenced pancreatic cells showed similar function when compared to non‐engineered cells, and they were protected against xenogeneic cellular and humoural responses (Carvalho Oliveira et al., 2020).…”

“…xenogeneic and allogeneic major histocompatibility complex (MHC) molecules, NK cells may not recognize sufficient inhibitory signals on the surface of xenogeneic cells as on allogeneic cells (Seebach et al, 1997;Sharland et al, 2002). However, some reports suggest that NK cells may not play a crucial role in the rejection of the xenograft (Benda et al, 1996;Carvalho Oliveira et al, 2020;Karlsson-Parra et al, 1996). In addition to the insufficient inhibitory markers recognition, NK cells may be activated by the interaction with activating ligands on xenogeneic cells, exacerbating the magnitude of the immune response towards the graft.…”