bims-hummad 2026-10-25 papers

Front Immunol. 2026 ;17 1782124

The CD160-HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation.

Shulin Sun, Lulin Ma.

Background: The clinical success of immune checkpoint blockade (ICB) in oncology has validated the existence of molecular brakes that restrain T-cell immunity. While releasing these brakes unleashes antitumour responses, their physiological role is to maintain self-tolerance. This review explores the reciprocal paradigm of the CD160-HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160-HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection.
Mechanisms: Unlike programmed cell death protein 1 (PD-1), CD160 operates within a bidirectional network involving herpesvirus entry mediator (HVEM; TNFRSF14), B- and T-lymphocyte attenuator (BTLA) and LIGHT (TNFSF14). The axis is expressed across lymphocytes, myeloid cells, epithelium, endothelium and malignant B cells. Mouse and human biology of the axis are not interchangeable: murine CD160 is a broad major histocompatibility complex (MHC) class I and CD1d receptor, whereas human natural killer (NK) triggering is dominated by HLA-C, and the transmembrane isoform CD160-TM is human-characterised. Structural diversity, from an inhibitory glycosylphosphatidylinositol (GPI)-anchored form to activating CD160-TM on NK cells, positions CD160 as a tunable rheostat rather than a linear checkpoint.
Therapeutic implications: While direct anti-CD160 candidates remain in advanced preclinical development, other components of the HVEM network are undergoing human clinical testing. The most mature clinical programme is tifcemalimab, an anti-BTLA monoclonal antibody, not an anti-CD160 agent. Antagonistic anti-HVEM antibodies (Demerlé anti-HVEM18-10 in humanised mice; preclinical fully human 4CB1, mechanistically related but distinct) block HVEM engagement by both BTLA and CD160. Because CD160 is inhibitory on T cells but activating on NK cells via CD160-TM, a systemic antibody to the shared ectodomain is a dual-function drug-design constraint, not a simple checkpoint blockade.
Conclusion: Precision use of this axis requires isoform, cell type, interaction geometry and disease context to be specified before a direction of intervention is chosen. Next steps are biomarker-qualified enrichment, isoform-discriminating reagents, and correlative CD160 profiling inside ongoing BTLA-HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.

Keywords: BTLA; CD160–HVEM axis; NK cell; T cell exhaustion; autoimmunity; clinical translation; transplantation

DOI: https://doi.org/10.3389/fimmu.2026.1782124

J Inflamm Res. 2026 ;19 641713

Question-Driven Selection of Psoriasis Animal Models: A Structured Narrative Review of 48 Model Records.

Tong Zhao, Xianbin Zhao, Donglian Du, Zehua Qin, Songqi Tang, Min Xiao.

Animal models connect psoriasis mechanisms to preclinical testing, but no model is informative for every question. This structured narrative review used PubMed, supplemented by reference-list screening and manual checks, to identify 29 original studies contributing 48 model records. One reviewer conducted screening and extraction, with targeted verification by a second reviewer. Within the selected records, IMQ- and IL-23-induced models primarily addressed acute inflammatory pathways, genetically engineered and composite models tested defined perturbations, humanized models examined human immune responses, and relapse models examined post-resolution reactivation. Composite designs were the largest category (22/48, 45.8%), whereas TRM were experimentally assessed in 6/48 (12.5%). We integrated model construction, disease-stage suitability and mechanism-evidence patterns into a conceptual question-driven framework linking prespecified objectives to candidate initial models, complementary validation and interpretation boundaries. The framework is a hypothesis-generating planning aid that has not undergone independent validation. Focused questions may be addressed with a single model, whereas complex mechanistic or translational questions require complementary models and comparison with human data.

Keywords: IL-23/IL-17 axis; animal model; imiquimod; preclinical model selection; psoriasiform dermatitis; psoriasis; tissue-resident memory T cells

DOI: https://doi.org/10.2147/JIR.S641713

iScience. 2026 Nov 20. 29(11): 117795

Bispecific antibodies targeting TL1A and IL-12/23p40 suppress pathogenic Th1/Th17 responses and ameliorate colitis in mice.

Xia Li, Hao Peng, Feng Hao, Yi Gu, Jinying Ning, Changyuan Yu.

Inflammatory bowel disease (IBD) remains a substantial therapeutic challenge, largely due to the limitations of single-target monotherapies. Here, we engineered two bispecific antibodies, KA-4316 and its half-life-extended derivative KA-5817, which co-target TL1A and IL-12/23p40 utilizing a common light chain design and knobs-into-holes Fc engineering. To improve clinical translatability, KA-5817 was modified with YTE Fc mutations to enhance FcRn binding. KA-4316 exhibited high binding affinity for both targets, high monomer purity, and favorable thermal stability. In vitro functional assays demonstrated that KA-4316 potently blocked TL1A-DR3 and IL-12/23p40-IL-12Rβ1 interactions, suppressing downstream signaling and pro-inflammatory cytokine release. In vivo, KA-5817 alleviated pathological severity in dextran sulfate sodium (DSS)-induced colitis in TL1A/IL23A/IL12B triple-humanized mice and showed a prolonged serum half-life in FcRn-humanized mice. KA-4316 and KA-5817 exhibit beneficial manufacturability and favorable biological activity. Our results support dual inhibition of TL1A and IL-12/23p40 as a potential therapeutic strategy for IBD.

Keywords: IL-12; IL-23; TL1A; bispecific antibodies; common light chain; inflammatory bowel disease

DOI: https://doi.org/10.1016/j.isci.2026.117795

Methods Mol Biol. 2027 ;3092 59-67

The Humanized Mouse Model of AGS: A Preclinical System for Analyzing Hypersensitivity to α-Gal and Potential Allergenic Epitopes.

Lorena Mazuecos.

Humanized mouse models are indispensable in vivo experimental platforms for investigating human-specific biological processes in a controlled and reproducible environment, serving as a preclinical link between basic research and application in translational research. Alpha-Gal syndrome (AGS) is one of the emerging pathologies that highlight the need for a murine system capable of mimicking the reproduction of key aspects of human immune and allergic responses. Humanized α1,3GalT-knockout (KO) mice have expanded research on immunological basis of the syndrome and advanced in preclinical research. Here we present a detailed experimental protocol of KO validation and studying α1,3GalT-KO in vivo immune responses to α-Gal and/or other epitopes or potential allergens.

Keywords: Allergen; Immune system; Mice; Red meat; Saliva; Tick; α-Gal

DOI: https://doi.org/10.1007/978-1-0716-5635-8_6

Cell. 2026 Oct 21. pii: S0092-8674(26)01201-8. [Epub ahead of print]

In vivo Gene Writing with engineered retrotransposons.

Efficient integration of gene-length cargos in vivo remains challenging. Non-long terminal repeat (non-LTR) retrotransposons, which naturally mobilize large DNA segments through an RNA intermediate, could potentially address these limitations. Here, we developed a computational pipeline to systematically identify a diverse set of non-LTR retrotransposons. Extensive engineering generated elements capable of the efficient and stable insertion of reporter genes in human cells using RNA templates introduced in trans, which we term Gene Writers. Gene Writers successfully generated CD19 and CD20 chimeric antigen receptor T (CAR-T) cells ex vivo with robust antitumor activity. Lipid nanoparticle-mediated RNA delivery enabled in vivo CAR-T cell generation and stable B cell depletion in a humanized mouse model. Our study delineates a comprehensive framework for the discovery, engineering, and application of non-LTR retrotransposons and demonstrates their utility for gene-sized cargo delivery in vivo, thereby bridging a critical gap in existing gene therapy modalities.

Keywords: LNP; cell and gene therapy; gene-length insertion; genome engineering; in vivo CAR-T engineering; in vivo RNA delivery; lipid nanoparticles; non-LTR retrotransposons; target-primed reverse transcription

DOI: https://doi.org/10.1016/j.cell.2026.09.054