KK2DP7 Stimulates CD11b+ Cell Populations in the Spleen to Elicit Trained Immunity for Anti-Tumor TherapyZhang, Tang, Wang
et alAdv Sci (Weinh) (2025)
Abstract: The induction of trained immunity for anti-tumor therapy represents an emerging frontier in immunotherapy research, though its mechanistic underpinnings remain poorly understood. Adjuvant-induced trained innate immune responses constitute a critical yet underexplored component of adjuvant mechanisms of action. Here, KK2DP7, a dendrimer-structured peptide derived from the immunomodulatory antimicrobial peptide DP7 (VQWRIRVAVIRK) is employed, as a model adjuvant to establish standardized protocols for investigating adjuvant efficacy and mechanisms in enhancing anti-tumor immunity via trained immunity. Initial studies revealed that KK2DP7 administration significantly delayed tumor growth post-inoculation in murine models. The comprehensive analysis demonstrated that splenic cells exhibited cardinal features of trained immunity, whereas splenectomized mice exhibited complete loss of this protective effect. Strikingly, the adoptive transfer of CD11b+ cells isolated from the non-lymphoid splenic compartment of KK2DP7-trained mice to naïve recipients conferred robust tumor suppression. Mechanistic investigations linked this phenomenon to TLR2-IRF7 axis activation and epigenetic reprogramming of CD11b+ cells, as evidenced by chromatin accessibility assays and histone modification profiling. These findings not only unveil a novel therapeutically actionable dimension of trained immunity, centered on spleen-resident CD11b+ cell reprogramming but also establish a standardized protocol framework for systematically investigating adjuvant mechanisms in the context of trained innate immunity.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
BCG-derived acellular membrane vesicles elicit antimycobacterial immunity and innate immune memoryYamaguchi, Samukawa, Matsumoto
et alFront Immunol (2025) 16, 1534615
Abstract: Tuberculosis (TB) is one of the leading causes of death due to infectious disease. The sole established vaccine against TB is the Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine. However, owing to the lack of durable immunity with the BCG vaccine and its risk of infection, safer vaccines that can also be used as boosters are needed. Here, we examined whether membrane vesicles (MVs) from BCG (BCG-MVs) isolated from BCG statically cultured in nutrient-restricted Sauton's medium (s-MVs) and from BCG planktonically cultured in nutrient-rich medium commonly used in the laboratory (p-MVs) could be used as novel TB vaccines. MVs are extracellular vesicles produced by various bacteria, including mycobacteria. Differences in the culture conditions affected the morphology, contents, immunostimulatory activity and immunogenicity of BCG-MVs. s-MVs presented greater immunostimulatory activity than p-MVs via the induction of TLR2 signaling. Mouse immunization experiments revealed that s-MVs, but not p-MVs, induced mycobacterial humoral and mucosal immunity, especially when administered in combination with adjuvants. In a BCG challenge experiment using BCG Tokyo type I carrying pMV361-Km, subcutaneous vaccination with s-MVs reduced the bacterial burden in the mouse lung to a level similar to that after intradermal vaccination with live BCG. Furthermore, the administration of s-MVs induced a significant lipopolysaccharide-induced proinflammatory response in macrophages in vitro. These results indicate that BCG-MVs obtained from static culture in Sauton's medium induce not only humoral immunity against mycobacteria but also trained immunity, which can allow the clearance of infectious agents other than mycobacteria. Together, these findings highlight the immunological properties of BCG-MVs and the availability of acellular TB vaccines that confer broad protection against various infectious diseases.Copyright © 2025 Yamaguchi, Samukawa, Matsumoto, Shiota, Matsumoto, Nakao, Hirayama, Yoshida, Nishiyama, Ozeki and Tomita.
Features of toll-like receptor genes (TLR-2, TLR-3, TLR-4 and TLR-6) polymorphism in open-angle glaucoma patientsShevchenko, Prokofiev, Konenkov
et alVavilovskii Zhurnal Genet Selektsii (2025) 29 (1), 128-134
Abstract: Modern research shows that innate immunity plays an important role in the pathogenesis of primary open-angle glaucoma (POAG). An increase in the content of toll-like receptors (TLR) in the glaucomatous retina of the human eye was revealed. TLRs can modulate the immune response in glaucoma; provide early recognition of damaging agents, activation of signaling pathways and effector mechanisms of the nonspecific immune defense system aimed at restoring homeostasis. The TLR-encoding genes' polymorphism alters the amino acid structure of the receptors, which leads to changes in their immune functions: expression level, ligand-binding and coreceptor functions, transport and signal transmission. The aim was to analyze the association of the TLR2 (rs5743708), TLR3 (rs3775291), TLR4 (rs4986790, rs4986791) and TLR6 (rs5743810) polymorphisms with primary open-angle glaucoma in patients of Western Siberia.99 patients (52 men and 47 women) with a diagnosis of primary open-angle glaucoma were examined. The comparison group consisted of 100 people (81 women and 19 men). TLR2 (rs5743708), TLR3 (rs3775291), TLR4 (rs4986790, rs4986791) and TLR6 (rs5743810) polymorphisms were analyzed by RT-PCR using test systems with Syber Green (Lytex, Russia). Statistical analysis was performed using the software package SPSS 23.0 and Arlequin 3.5.2.2.the distribution of genotypes in the patient group and in the control group corresponded to the Hardy-Weinberg equilibrium. The genotype frequencies did not significantly differ between the two analyzed groups. The frequency of TLR2-753 ArgArg:TLR6-249 ProPro was increased in the group of patients with POAG. The linkage disequilibrium between two polymorphic positions of the TLR4 gene was revealed. In addition, the linkage disequilibrium between TLR2-TLR6 gene for the glaucoma group and the control group was revealed.an increase in certain genotypes in the patient group relative to the control group may indirectly indicate the involvement of infectious factors in the initiation of POAG. However, despite the proven importance of the participation of their protein products in the pathogenesis of glaucoma, the relationship of TLR polymorphism requires additional research taking into account the ethnic characteristics of patients and intergenic interactions for a better understanding of the complex mechanisms of disease development. This will help carry out early diagnosis and develop the necessary therapeutic strategy.Copyright © AUTHORS.
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