Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

Kooreman, Nigel G.; Almeida, Patrícia E. de; Stack, J.; Nelakanti, Raman; Diecke, Sebastian; Shao, Ning‐Yi; Swijnenburg, Rutger-Jan; Sánchez-Freire, Verónica; Matsa, Elena; Li, Chun; Connolly, Andrew J.; Hamming, Jaap F.; Quax, Paul H.A.; Brehm, Michael A.; Greiner, Dale L.; Shultz, Leonard D.; Wu, Joseph C.

doi:10.1016/j.celrep.2017.08.003

Cited by 33 publications

(37 citation statements)

References 43 publications

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“…Metrics for assessing rejection/tolerance of PSC therapies, in humanized mice and other models, vary among research groups and cell types ( de Almeida et al., 2014 , Kooreman et al., 2017 , Sugita et al., 2016 , Zhao et al., 2011 ). Progression of the field will require cell-type-specific criteria, informed by clinical solid organ transplantation guidelines ( Haas, 2016 , Solez et al., 1993 ).…”

Section: Resultsmentioning

confidence: 99%

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

et al. 2018

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SummaryHere, we describe the NeoThy humanized mouse model created using non-fetal human tissue sources, cryopreserved neonatal thymus and umbilical cord blood hematopoietic stem cells (HSCs). Conventional humanized mouse models are made by engrafting human fetal thymus and HSCs into immunocompromised mice. These mice harbor functional human T cells that have matured in the presence of human self-peptides and human leukocyte antigen molecules. Neonatal thymus tissue is more abundant and developmentally mature and allows for creation of up to ∼50-fold more mice per donor compared with fetal tissue models. The NeoThy has equivalent frequencies of engrafted human immune cells compared with fetal tissue humanized mice and exhibits T cell function in assays of ex vivo cell proliferation, interferon γ secretion, and in vivo graft infiltration. The NeoThy model may provide significant advantages for induced pluripotent stem cell immunogenicity studies, while bypassing the requirement for fetal tissue.

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Section: Resultsmentioning

confidence: 99%

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

et al. 2018

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“…In human immune system-humanized mouse models, the immunodeficient mouse spleen is reconstituted with human immune cells to generate a humanized murine spleen; however, human immune cell reconstitution and associated red pulp and lymphoid follicle development in the humanized murine spleen is not optimal (13). The suboptimal human immune cell reconstitution of the humanized murine spleen in human immune system-humanized mouse models is exhibited by the disorganized splenic architecture and associated low red pulp macrophage reconstitution, which -in contrast -is the most abundant cell type in the human spleen (14).…”

Section: Introductionmentioning

confidence: 99%

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Samal¹,

Kelly²,

Na-Shatal³

et al. 2018

JCI Insight

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A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation. Said model will enable in vivo mechanistic studies, thus complementing the well-established surrogate model of SIV infection-induced lymphoid tissue fibrosis in macaques. We developed a potentially novel human immune system-humanized mouse model by coengrafting autologous fetal thymus, spleen, and liver organoids under the kidney capsule, along with i.v. injection of autologous fetal liver-derived hematopoietic stem cells, thus termed the BM-liver-thymus-spleen (BLTS) humanized mouse model. BLTS humanized mouse model supports development of human immune cells and human lymphoid organoids (human thymus and spleen organoids). HIV infection in BLTS humanized mice results in progressive fibrosis in human lymphoid tissues, which was associated with immunodeficiency in the lymphoid tissues, and lymphoid tissue fibrosis persists during ART, thus recapitulating clinical outcomes.

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“…In order to integrate the data obtained from different tissues and evaluate the immunization responsiveness among them, we adopted a classification machine learning algorithm based on an artificial neural network (ANN). A Principal Component Analysis (PCA) ( 26 , 27 ) was further used to reduce the critical information required to predict responsiveness from the ANN ( 28 ). The markers pinpointed by the PCA revealed that the correlation structure of organ-specific markers is strongly impacted by immunization and, therefore, that these markers can be used as biomarkers to retrieve the information of the immunization status.…”

Section: Introductionmentioning

confidence: 99%

Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization

et al. 2017

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Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses in vivo. Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8+ T cell responses in NOD.Cg-Rag1tm1Mom-Il2rγtm1Wj humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8+ memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses in vivo. A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation.

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Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

Cited by 33 publications

References 43 publications

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization

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