bims-hummad 2026-09-06 papers

Front Immunol. 2026 ;17 1887623

Development of humanized mouse models for the preclinical evaluation of NK cell-based therapies.

Pauline Rettman, Samira Benhamouche-Trouillet, Georges A Azar, Dorothée Bourges, Valeria Fantin, Sukhvinder S Sidhu, Céline Nicolazzi.

Introduction: Novel immunotherapeutic strategies engaging human Natural Killer (huNK) cells have emerged as a promising treatment paradigm; however, their accurate preclinical evaluation requires reliable mouse models capable of supporting functional huNK cell engraftment.
Methods: We developed and characterized robust in vivo NK-humanized mouse models using immunodeficient human Interleukin-15 (huIL-15) transgenic (Tg) mice. In vitro amplified huNK cells were used as the source of immune cells. Multiple humanized mouse models were evaluated with optimized protocols. Fcγ receptor knocked-out (FcγR-KO) mice were employed to exclusively model antibody-dependent cellular cytotoxicity (ADCC) potential of huNK cells. A resting period prior to adoptive transfer was also introduced and assessed.
Results: Our NK-humanized mouse models were developed using in vitro amplified huNK cells, which facilitated the production of large number of viable and functional huNK cells and allowed the engraftment of greater cohort of mice. We identified several key parameters improving the long-term persistence and proliferation of functional huNK cells that maintain important functional cell surface markers. FcγR-KO mice exclusively modeled the ADCC potential of huNK cells without the confounding contribution of mouse immune cells. The introduction of a pre-transfer resting period improved tolerability and circumvented potential donor-dependent toxicity issues. Engrafted huNK cells were successfully mobilized in vivo by different NK-based therapeutics, including an engineered IL-2 and an ADCC-enhanced monoclonal antibody.
Discussion: The NK-humanized huIL-15 Tg mouse models developed here provide a versatile and translationally relevant platform for the evaluation and selection of NK cell-based drug candidates, improving clinical translatability and offering a robust framework for preclinical assessment of novel NK cell immunotherapies.

Keywords: NK cell-based therapies; NK-humanized mouse model; Natural Killer cells; huIL-15 transgenic mice; in vivo models; monoclonal antibodies

DOI: https://doi.org/10.3389/fimmu.2026.1887623

Methods Mol Biol. 2026 ;3053 69-89

Generation and Use of an Alloantigen-Specific Preclinical Humanized Mouse Model of Fetal and Neonatal Alloimmune Thrombocytopenia.

Huiying Zhi, Debra K Newman, Peter J Newman.

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies targeting a paternally inherited alloantigen present on the surface of fetal platelets. The human platelet alloantigen HPA-1a/HPA-1b, also known as the PlA1/PlA2 alloantigen, is the most frequently implicated HPA for causing FNAIT in Caucasians. A single Leu33Pro amino acid polymorphism residing within the plexin/semaphorin/integrin (PSI) domain of the integrin β3 subunit (platelet membrane glycoprotein (GP), GPIIIa) is responsible for generating the HPA-1a and HPA-1b epitopes. In mice, the GPIIIa gene encodes a glutamine at position 33, making it challenging to model the alloimmune response, thereby hindering studies on the underlying mechanisms and therapeutic interventions of this alloimmune disorder. This chapter outlines the development and use of a humanized, alloantigen-specific preclinical mouse model of FNAIT, aiming to advance basic and translational research in this field. Basic protocols are provided for (1) generating an HPA-1a transgenic mouse by introducing humanized residues A30P32L33D39 within the PSI domain and Q470 in the EGF1 domain of mouse integrin β3 using CRISPR/Cas9 gene editing technology, (2) developing a preclinical alloantigen-specific humanized mouse model of FNAIT using the HPA-1a transgenic APLDQ mice, and (3) examining the efficacy of a prophylactic treatment regimen in preventing alloimmunization and FNAIT development using this alloantigen-specific mouse model. This humanized mouse model faithfully recapitulates many clinically important aspects of human FNAIT, serving as a valuable tool for studying the pathophysiological mechanisms underlying the alloimmune response and assessing prophylactic and therapeutic interventions in translational research.

Keywords: Alloimmune response; Fetal/neonatal alloimmune thrombocytopenia (FNAIT); Human platelet alloantigen (HPA); Humanized mouse model; Integrin β3 subunit; Therapeutic reagents

DOI: https://doi.org/10.1007/978-1-0716-5376-0_4

Glob Health Med. 2026 Aug 31. 8(4): 253-264

Effectiveness of human induced pluripotent stem cell-derived β-like cell/islet transplantation in animal models of diabetes: A meta-analysis of preclinical studies.

Ruijie Cai, Junming Xu, Xiaopu Sang, Jie Ke, Guoqing Wu, Ning Li, Tetsuya Asakawa, Fenfang Wu.

Emerging approaches in regenerative medicine for the treatment of diabetes have attracted attention. This meta-analysis aimed to evaluate the effectiveness of human induced pluripotent stem cell (hiPSC)-derived β-like cell/ islet transplantation in animal models of diabetes. Studies using strictly controlled designs to assess hiPSC-derived β-like cell/islet transplantation were included. A reduction in blood glucose (BG) levels and improvement on the glucose tolerance test (GTT) served as indices to assess effectiveness. Twelve studies published between January 1, 2016 and December 31, 2025 were included. Pooled evidence indicates that transplantation of hiPSC-derived β-like cells/ islets is associated with significant reductions in BG levels from four weeks to two months post-transplantation, with hypoglycemic effectiveness tending to increase over time. Improvements in glucose tolerance were also consistently observed. Overall, this meta-analysis synthesizes current preclinical evidence and identifies key areas where further research is needed to clarify translational and potential clinical applications.

Keywords: diabetes; hiPSC derived β-like cells; hypoglycemic effects; islet; regenerative medicine

DOI: https://doi.org/10.35772/ghm.2026.01008