Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation

Abstract

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

Development of a Hallmark Pathway-Related Gene Signature Associated with Immune Response for Lower Grade Gliomas

“…It was found that an innate immune mechanism emerged in the AR and proinflammatory cytokines activated by innate immune-stimulated T cell expansion during this pathway process [ 22 ]. Meanwhile, Ashwin et al observed that AR was an unregulated pathway in the immune response, and Subhayan et al detected that this pathway was related to the B cell receptor signaling pathway [ 23 , 24 ]. The association between AR and gliomas has been reported.…”

Patient-derived xenograft (PDX) models, applications and challenges in cancer research

“…One of these approaches is to create humanized mouse models. These models are engrafted with human cells and tissues that impart human characteristics to mice and make the model a valuable tool for clinical translation [ 7 ]. The humanized mouse models mimic the human immune system; therefore, these models are mainly used to create patient-derived xenograft (PDX) models for cancer studies.…”

Lactate oxidase nanocapsules boost T cell immunity and efficacy of cancer immunotherapy

“…Thus, controlling the H 2 O 2 concentrations upon systematic injection of n(LOx) will be an essential issue, which may be addressed by coadministrating CAT ( 40 ). We also note that the currently available humanized models have the limitation of human leukocyte antigen mismatch between the tumor and the human immune cells, which may induce treatment-independent immune response to tumor cells ( 41 ). Therefore, the evaluation and conclusions of therapeutic efficacy in humanized mice with tumor xenograft need to be carefully interpreted and supported by results in immunocompetent mice.…”