bims-hummad 2026-03-01 papers

Animal Model Exp Med. 2026 Feb 26.

A humanized NOG-EXL mouse model for producing severe fever with thrombocytopenia syndrome virus-reactive human antibodies.

Dong Hoon Lee, Jiyeong Bae, Sumi Kim, Chan Young Song, Jung Hyu Shin, Eun Hee Kim, Chan Ho Jang, Young-Sun Yun, Dong-Sook Lee, Hyuk Chu, Jang-Hoon Choi, Chan Woo Kim.

BACKGROUND: Humanized mouse models are essential for studying the human immune response and antibody development. However, conventional models show limited B cell maturation and antigen-specific humoral responses. To overcome these limitations, we used the NOG-EXL mice expressing human interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance myeloid and B-cell lineage differentiation.
METHODS: Human CD34+ hematopoietic stem cells (HSC) were transplanted into NOG-EXL mice to produce humanized immune systems. After immune cell reconstitution was confirmed across 12 weeks, the mice were immunized twice with inactivated severe fever with thrombocytopenia syndrome virus (SFTSV) antigens. Peripheral blood mononuclear cells and splenocytes were analyzed using multicolor flow cytometry to assess human immune cell subsets. Antigen-specific immunoglobulin G (IgG) production was quantified using enzyme-linked immunosorbent assay (ELISA), and virus-specific B cells were isolated using antigen-labeled recombinant protein probes.
RESULTS: Twelve weeks after transplantation of HSCs into NOG-EXL mice, they exhibited robust engraftment of human leukocytes, including T, B, and dendritic cells, compared to NOG mice. Unlike NOG mice, humanized NOG-EXL mice exhibited an increase in human IgG levels, indicating the production of human antibody responses to antigens. Humanized NOG-EXL mice were immunized twice every 2 weeks with inactivated SFTSV, and antigen-specific human antibodies against the virus were detected in the mouse sera by ELISA. Sera from SFTSV-immunized humanized mice demonstrated neutralizing activity against SFTSV, confirming the induction of functional virus-specific neutralizing antibodies. Antigen-binding IgG-positive human B cells were isolated from mouse splenocytes using recombinant protein probes.
CONCLUSION: This model provides a valuable platform for evaluating humoral immunity and isolating B cells using high-affinity human monoclonal antibodies without genetic engineering.

Keywords: human immunoglobulin G (IgG); humanized mouse; severe fever with thrombocytopenia syndrome virus (SFTSV)

DOI: https://doi.org/10.1002/ame2.70140

Genes (Basel). 2026 Jan 31. pii: 170. [Epub ahead of print]17(2):

Using HLA-DR3-CBA/J Humanized Mice to Develop a Novel Genetic Model for Autoimmune Thyroiditis.

Aizhan Kozhakhmetova, Mihaela Stefan-Lifshitz, Olga Meshcheryakova, Yaron Tomer.

BACKGROUND: Experimental autoimmune thyroiditis is an important animal model for studying Hashimoto's thyroiditis. Our aim was to develop the model using CBA/J-DR3 mice expressing human HLA-DR3, which is associated with autoimmune thyroiditis in humans, to better simulate human autoimmune thyroiditis. Such a humanized model can be used to test specific antigen therapies for autoimmune thyroiditis.
METHODS: CBA/J-DR3 mice were produced by back-crossing B6-DR3 mice to the CBA/J background. Female CBA/J-DR3 mice were immunized with human thyroglobulin (Tg) in complete Freund's adjuvant on days 0 and 7. On day 21, mice were sacrificed, blood collected, spleen and thyroid harvested for analysis. Splenocytes were analyzed for T cell responses to Tg and its major T-cell epitope in human autoimmune thyroiditis, Tg.2098. Serum anti-thyroglobulin antibodies were measured by ELISA, and thyroid-stimulating hormone was measured using the Luminex assay. Thyroid histology and immunohistochemistry were examined.
RESULTS: Immunized CBA/J-DR3 mice showed significant T cell proliferation in response to Tg (stimulation index 3.4 ± 4.5) and Tg.2098 (1.5 ± 0.7). Anti-thyroglobulin antibody levels were elevated in immunized mice when compared to control mice (2.05 ± 0.75 vs. 0.15 ± 0.06, p < 0.0001). T cells demonstrated higher reactivity to thyroid antigens by enhanced production of pro-inflammatory cytokines. Thyroid immunohistochemistry revealed mild CD3-positive T-cell infiltration.
CONCLUSIONS: This novel humanized CBA/J-DR3 mouse model of Hashimoto's thyroiditis demonstrates key features of human autoimmune thyroiditis. The HLA-DR3 background and the immune response to Tg and Tg.2098 enhance translational relevance, making this a valuable model for studying thyroid disease pathogenesis and testing targeted immune-modifying therapies.

Keywords: T cells; autoimmune thyroiditis; mouse model; thyroglobulin; thyroid

DOI: https://doi.org/10.3390/genes17020170

Sci Transl Med. 2026 Feb 25. 18(838): eadz0672

A peptide immunomodulator activates MST1 to expand and stabilize murine and human regulatory T cells for immune tolerance.

Yu Wang, Xinnan Liu, Xiaoxue Li, Linfeng Zhao, Hongli Chen, Xuyan Gong, Junji Xu, Jian Zhang, Zhiduo Liu, Yao Sun.

The expansion and potentiation of regulatory T cells (Treg cells) offer an appealing approach for achieving immune tolerance and controlling overactive immune responses across a range of diseases. Current therapeutic approaches to expanding and improving function of Treg cells have predominantly relied on protein-based biologics, such as recombinant interleukin-2 (IL-2); in contrast, peptide-based interventions that can expand Treg cells with improved functional stability, enhanced specificity, and favorable safety profiles remain underexplored. Here, using a deep learning model, we identified a hexapeptide (DLST-6P) that preferentially expands both human and murine Treg cells while preserving their stability. When tested in multiple autoimmune and inflammatory disorders, including a humanized mouse model of graft-versus-host disease, DLST-6P exhibited therapeutic efficacy both as a monotherapy and in combination with low-dose IL-2. Mechanistically, we found that DLST-6P directly targets and activates mammalian Ste20-like kinase 1 (MST1) by promoting homodimer formation. After activation by DLST-6P treatment, MST1 phosphorylated the master Treg cell transcription factor forkhead box protein P3 (FOXP3) at serine-390. This promoted the association of FOXP3 with the acetyltransferase tat-interacting protein 60, leading to enhanced FOXP3 acetylation and protein stabilization. Simultaneously, we observed that DLST-6P-mediated activation of MST1 alleviated suppressor of cytokine signaling-mediated inhibition of IL-2 signaling in Treg cells, thereby sensitizing the cells to IL-2 stimulation. Together, these findings unveil a dual mechanistic program through which pharmacological activation of MST1 can boost Treg cell expansion and stability and highlight the translational potential of DLST-6P as a peptide-based immunomodulator for treating autoimmune and inflammatory disorders.

DOI: https://doi.org/10.1126/scitranslmed.adz0672

bioRxiv. 2026 Feb 20. pii: 2026.02.19.706929. [Epub ahead of print]

A universal platform for simultaneous TCRα/β removal enables safer and more potent TCR therapies and autoimmune modeling.

Giorgia Zanetti, Mateusz Legut, Austin Chen, Farshid Fathi, Nathan Suek, Nato Teteloshvili, Hao Wei Li, Xiaolan Ding, Daniel Traum, Klaus H Kaestner, Ryan E Hoang, Edwin Bremer, Andrew K Sewell, Audrey V Parent, Remi J Creusot, Megan Sykes, Mohsen Khosravi-Maharlooei.

Adoptive T-cell therapies using tumour-specific T-cell receptors (TCRs) are limited by competition with endogenous receptors, which impairs efficacy and poses risks of off-target autoreactivity. Here we present a CRISPR-based platform that completely and selectively eliminates both endogenous TCR-α and -β chains without affecting introduced transgenic TCRs, irrespective of codon optimization. This approach achieves >90% deletion efficiency in Jurkat and primary human T cells, markedly enhancing the expression, pairing fidelity, and functional potency of transgenic receptors. Using a clinically relevant HLA-A*02:01-restricted DMF5 TCR, we show that dual TCR ablation boosts antigen-specific activation and cytotoxicity in vitro and significantly enhances tumor clearance in vivo in human immune system (HIS) mice, while preventing graft-versus-host disease (GVHD). Targeted locus amplification revealed that CRISPR-induced double-strand breaks did not alter lentiviral integration profiles, confirming genomic safety. Extending this approach to four insulin-reactive TCRs demonstrated that removal of endogenous receptors increased transduction efficiency and functional activity, with one (1E6) showing selective activation and infiltration of stem cell-derived islet grafts (SC-islets) in vivo . This study establishes a universal, safe, and scalable genome-editing platform for generating functionally precise human T cells. By integrating cancer immunotherapy and autoimmune disease modelling within a single framework, it provides a strong preclinical rationale for dual endogenous TCR removal as a route to improved specificity, safety, and therapeutic efficacy in TCR-based cell therapies.

DOI: https://doi.org/10.64898/2026.02.19.706929