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However, NOG mice showed a remarkably higher xenoengraftment level compared with NOD- scid mice despite having the NOD background. These reports indicated that the NOD strain is much better than other strains in engrafting human cells and tissues. ( 14) reported that complement-dependent hemolytic activity is more severely impaired in the NOD strain than in other inbred strains. ( 13) reported that the SIRP-α polymorphism on the NOD genetic background leads to enhanced binding to human CD47 and that this interaction may activate CD47-induced signaling pathways to support xenoengraftment. The recently reported signal regulatory protein-α (SIRP-α), which is a critical immune inhibitory receptor on macrophages, interacts with the CD47 ligand on the xenograft to prevent phagocytosis ( 10– 12). The NOD strain in combination with the scid mutation or RAG deficiency is known to promote xenoengraftment. The current results suggest that CD11c +B220 +CD122 + cells play an important role in xenograft rejection, and their absence in NOG mice may be critical in supporting the successful engraftment of xenotransplants. Moreover, the CD122 + cells in the pDC fraction were morphologically distinguishable from conventional CD122 + NK cells and showed a higher rejection efficiency. The CD11c +B220 +CD122 + cells further fractionated from the pDCs based on the expression of CD122, which is an NK cell marker strongly inhibited during hPBMC engraftment in NOG mice. These experiments revealed that CD11c +B220 + plasmacytoid dendritic cells (pDCs) from NOD- scid mice markedly inhibited engraftment of human cells. To identify the cell types responsible for this effect, we transferred subpopulations of spleen cells from NOD- scid mice into NOG mice and assessed the levels of human cell engraftment after human PBMC (hPBMC) transplantation. These results indicate that cell types other than splenic NK cells present in NOD- scid mice but not in NOG mice may be involved in this suppression. This high engraftment rate of xenotransplants in NOG mice was substantially suppressed by the transfer of spleen cells from NOD- scid mice that were devoid of NK cells. NOD/Shi- scid-IL2rγ null (NOG) mice are known to show an extremely high engraftment rate of xenotransplants compared with conventional immunodeficient mice. 2004 112(3):273–283.Xenograft animal models using immunodeficient mice have been widely applied in medical research on various human diseases. Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1(null)Prf1(null) mice. 2008 13(6):633–638.īanuelos SJ, Shultz LD, Greiner DL, Burzenski LM, Gott B, Lyons BL, Rossini AA, Appel MC. Causes of limited survival of microencapsulated pancreatic islet grafts. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, Philips R. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.Ĭalafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, Racanicchi L, Mancuso F, Brunetti P. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. This warrants the need for a suitable small animal model. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level.