bims-hummad 2026-08-02 papers

Biology (Basel). 2026 Jul 10. pii: 1125. [Epub ahead of print]15(14):

Murine and Humanized Mouse Models in Autoimmune Disease Research and Therapeutics Development.

Sameena Nikhat, Suman Bose, Mohsen Khosravi-Maharlooei.

Autoimmune diseases arise from a breakdown of immune tolerance and complex interplay of genetic susceptibility, environmental triggers, tissue-specific immune responses, microbiota, and regulatory pathways. Mouse models remain essential for dissecting these mechanisms, but no single model fully reproduces the heterogeneity, chronicity, and immune complexity of autoimmune disease in humans. This review summarizes classical murine and humanized mouse models used to study inflammatory bowel disease (IBD), multiple sclerosis (MS), type-1 diabetes (T1D), and rheumatoid arthritis (RA). We also highlight disease-specific scoring systems, including clinical indices, histopathology, imaging, cytokine profiling, autoantibody assessment, and human immune-cell readouts, as essential tools for standardized interpretation. Conventional murine models provide experimental control and mechanistic clarity, whereas humanized models improve assessment of human immune responses, patient-specific biology, and therapeutic translation. However, humanized systems remain limited by incomplete immune reconstitution, graft-versus-host disease, donor variability, cost, and incomplete tissue architecture. By providing a comparative framework spanning both conventional and humanized models, this review aims to guide informed model selection tailored to specific research questions in autoimmune disease biology and translational therapeutic development.

Keywords: adaptive immunity; animal models; autoimmune disease; human immune system (HIS); humanized mice; immune tolerance; inflammatory bowel disease; multiple sclerosis; rheumatoid arthritis; type-1 diabetes

DOI: https://doi.org/10.3390/biology15141125

Front Immunol. 2026 ;17 1852823

Neonatal and pediatric thymic grafts generate similar human T-cell chimerism in humanized mice.

Natalia M Del Rio, Liupei Huang, Alexis M Holm, Wesley Blashka, Nicholas A Smith, Sayandeep Saha, Adam J Bell, Janell Richardson, Katherine E Badior, Christian J Kastrup, Matthew E Brown.

Human immune system (HIS) humanized mice, particularly those incorporating human thymic tissue and hematopoietic stem/progenitor cell (HSPC) co-transplantation, provide a powerful in vivo platform to study human T-cell development, tolerance, and effector function in the context of a full human immune system. The thymus is a lymphoid organ that is indispensable for generating a diverse and self-tolerant T-cell repertoire, and its inclusion in HIS models is essential for generating human major histocompatibility complex-restricted T cells. The bone marrow-liver-thymus (BLT) HIS model is made using human fetal tissues of a very narrow gestational age, typically 17-22 weeks. We previously developed the NeoThy™ humanized immune system mouse model, which is created using cord blood HSPCs and donated thymus tissue from neonatal and pediatric donors, as a non-fetal alternative to the BLT model. While the BLT model uses tissue of relatively consistent gestational age, further study is needed to assess the impact of the thymic donor age in the NeoThy model, since thymic tissue donors can range from a few days old to many years old. Here, we created multiple cohorts of NeoThy mice using thymic tissue from donors of various ages and compared them to each other and to cohorts of BLT mice. In the NeoThy mouse cohorts, we confirmed de novo thymopoiesis within transplanted human thymic grafts. Across multiple independent experiments encompassing both neonatal and pediatric thymic donors, we observed similar T-cell chimerism and function, regardless of thymic donor age. Inter-donor variability, an inherent feature of all HIS mouse models, accounted for observed differences in immune engraftment kinetics. T cells developing in the presence of a transplanted thymus exhibited gene expression signatures consistent with more mature functional responses to mRNA vaccine challenge than those observed in mice receiving cord blood only. These findings highlight the importance of including thymic transplantation in this context and confirm that both neonatal and pediatric thymus donor tissue are capable of generating robust chimeric immune systems in HIS mice.

Keywords: BLT mouse; NeoThy mouse; humanized mouse; mRNA vaccine; thymopoiesis; thymus transplantation

DOI: https://doi.org/10.3389/fimmu.2026.1852823

bioRxiv. 2026 Jul 16. pii: 2026.07.10.737744. [Epub ahead of print]

The NBSGW RIP-DTR Mouse: An Integrated Platform for Diabetes Induction, Human Immune Reconstitution and Transplantation Studies.

Connie S Chamberlain, Deep Kapadia, Ellen Abad Santos, Liupei Huang, Alexis M Holm, Caterra Leavens, Ayesha Palwasha-Khan, Katherine M Gorski, Colin C Steck, Anna Mikat, Daniel M Tremmel, Peter Chlebeck, Kayla Talerico, Esau Estrada, Brian McIntosh, Matthew E Brown, Sara Dutton Sackett, Jon S Odorico.

Using toxin receptor-mediated cell ablation, a diabetes mouse model was generated that supports engraftment of human hematopoietic stem/progenitor cells (HSPCs) without the need for irradiation. The NBSGW immunodeficient strain was crossed with the NSG RIP-DTR which carries the diphtheria toxin receptor (hDTR) under the control of the rat insulin promoter to generate the NBSGW RIP-DTR mouse. This model enables controlled β-cell ablation, robust human immune system reconstitution without myeloablative conditioning, and evaluation of human immune-mediated graft rejection within a single platform. NBSGW RIP-DTR mice exhibited reproducible and titratable diabetes induction, supported durable human islet engraftment and glycemic correction, and retained efficient human hematopoietic reconstitution comparable to the parental NBSGW strain. In humanized mice, diphtheria toxin-mediated diabetes induction was well tolerated and enabled assessment of human immune responses to allogeneic islet grafts. Collectively, these findings establish the NBSGW RIP-DTR mouse as an integrated and clinically relevant platform for studying β-cell replacement therapies and human immune-mediated graft rejection.
Article Highlights: Current preclinical models do not simultaneously support controlled diabetes induction, human islet transplantation, and durable human immune reconstitution without irradiation.This study asked whether the NBSGW RIP-DTR mouse could integrate diphtheria toxin-mediated β-cell ablation with irradiation-free humanization in a single platform.NBSGW RIP-DTR mice demonstrated reproducible diabetes induction, supported functional human islet engraftment, and retained robust human hematopoietic reconstitution comparable to parental strains.These findings establish the NBSGW RIP-DTR model as a clinically relevant platform for studying β-cell replacement and human immune response to islet allografts, xenografts and stem cell-derived islets.

DOI: https://doi.org/10.64898/2026.07.10.737744

Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2600260123

Calcitriol-PKM2 axis drives transcriptional and metabolic reprogramming of ILCPs into intestinal dual-cytokine-producing ILC3s.

Qingyang Liu, Yidan Wang, Yanxiu Li, Yiyan Wang, Wei Liu, Steven Rosen, Fang Liang, Tingting Xie, Yang Xia.

Vitamin D deficiency is associated with dysregulated alloimmune responses, but the mechanisms by which its active metabolite calcitriol shapes innate lymphoid cell (ILC) development and function remain incompletely understood. Here, we elucidate how calcitriol directs the differentiation of bone marrow (BM) ILC progenitors (ILCPs) into anti-inflammatory ILC3s with therapeutic potential in alloimmune diseases. Using murine vitamin D models, integrated omics, 13C-glucose tracing, humanized mouse models, and clinical samples, we show that calcitriol, through the vitamin D receptor (VDR), selectively promotes the expansion and differentiation of BM ILCPs into IL-10+IL-22+ ILC3s that exert tissue-protective effects in the intestine. Calcitriol-primed BM ILCP cell therapy attenuates intestinal inflammation in an alloimmune setting. Mechanistically, a VDR-SYK axis triggers nuclear translocation of pyruvate kinase M2 (PKM2). Nuclear PKM2 phosphorylates STAT3 at Tyr705, forming a dimerization complex with c-JUN that drives Il10 transcription. Simultaneously, cytosolic PKM2 channels pyruvate into pyruvate carboxylase-mediated mitochondrial anaplerosis, sustaining oxidative phosphorylation while suppressing reverse electron transport-driven mitochondrial ROS production. In human studies, patients with severe alloimmune complications exhibit reduced circulating ILCPs and low serum 25(OH)D levels. Calcitriol-treated human CD117+ ILCPs efficiently generate IL-10-producing ILCs in vitro and in humanized models, potently suppressing alloreactive T cell responses. Collectively, calcitriol reprograms BM ILCPs via the VDR-SYK-PKM2 axis to generate dual-cytokine IL-10+IL-22+ ILC3s, establishing PKM2 as a key immunometabolic target and supporting calcitriol-primed ILCP-based cell therapy as a promising approach for alloimmune diseases.

Keywords: PKM2; alloimmune responses; cell therapy; immunometabolism; innate lymphoid cells

DOI: https://doi.org/10.1073/pnas.2600260123