Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models

Abstract

Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed.

Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model

“…4 A). We have beforehand observed that tacrolimus substantially prolonged the liver organoid survival in this model [ 38 ], indicating that T cell-mediated immune reaction is at least partially responsible for the loss of iPSC-derived allogeneic grafts. As tacrolimus could solely regulate the rejection as described above, TDC-based treatment could not be evaluated with this model.…”

“…Thus, in this study, we focused on the therapeutic potential of CB-based treatment. Humanized mice generation and liver organoid transplantation were carried out following procedures we have previously described [ 38 ]. Given that one of the reported limitations of the humanized mice is an insufficient lymphoid immune response due to poor lymph node development [ 39 , 40 ], we used HLA haplotype A mismatched combination in this experiment.…”

Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice

“…As a result, the study window was brief in view of the limited life span of these animals. Nevertheless, an observation period of 6–8 weeks is adequate for the development of allogenic immune responses [ 32 ]. Throughout the follow-up period, the animals weight, blood sugar levels and serum levels of human and/or mouse insulin were measured.…”

A Novel Orthotopic Liver Cancer Model for Creating a Human-like Tumor Microenvironment

“…Male, 7-week-old non-obese diabetic/Shi-scid, IL-2RγKO Jic (NOG) mice (In-Vivo Science Inc., Tokyo, Japan), female humanized mice [37], NOG-HLA-A2 transgenic mice (In-Vivo Science Inc., Tokyo, Japan), female 10-week-old NOD-SCID mice (Sankyo Labo Service Corporation, Inc. (Tokyo, Japan)) were used in this study. All animal experiments were conducted following the ethics regulations established by the Animal Experiment Committee of Yokohama City University, and the Animal Experiment Committee approved the animal experiment methods (approval No.…”