The S1P1 regulator IMMH002 and its therapeutic effect and mechanism on autoimmune hepatitis / 药学学报

This study assessed and explored the pharmacological effects and mechanisms of action of IMMH002 {2-amino-2-(2-(4ʹ-(2-ethyloxazol-4-yl)-[1,1ʹ-biphenyl]-4-yl)ethyl)propane-1,3-dio}, a selective sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, in a concanavalin A (ConA)-induced autoimmune hepatitis (AIH) mouse model. The experimental protocol strictly adhered to the guidelines of the Ethics Committee for Animal Research of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No.: 00004046). Male ICR mice were pre-treated with the drug for four days, followed by induction of AIH through tail vein injection of ConA protein. Liver function, hepatic tissue pathology, peripheral blood parameters, as well as immunoglobulin G (IgG), inflammatory cytokines, T cell distribution, and inflammatory pathways were evaluated in mice. Results demonstrated that IMMH002 significantly reduced liver function indicators such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated hepatic tissue inflammation and necrotic damage, decreased serum IgG levels, and lowered the expression of inflammatory mediators including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). Additionally, it facilitated T lymphocyte homing, downregulated the phosphorylation of nuclear factor kappa-B (NF-κB), IκB kinase β (IKKβ) and nuclear factor inhibitor protein-α (IκBα) proteins in hepatic tissue and cellular inflammation models. Collectively, IMMH002 effectively ameliorated ConA-induced autoimmune hepatitis in mice, exhibiting extensive anti-inflammatory and anti-necrotic effects, thereby laying a theoretical foundation for AIH clinical treatment.

S1P/S1P Receptor Pathway: A New Target for Treatment of Inflammatory Bowel Disease / 胃肠病学

The development of targeted oral drugs that can stably treat inflammatory bowel disease (IBD) is still a clinical problem to be solved. In recent years, studies have confirmed that sphingosine⁃1⁃phosphate (S1P)/S1P receptor pathway can regulate lymphocyte homing and immune regulation, inhibit intestinal inflammation, protect intestinal endothelial barrier, and affect intestinal microbial metabolism, which may play a key role in the treatment of IBD. This article reviewed the effect of S1P/S1P receptor pathway on IBD and its potential mechanism.

T lymphocyte homing: a critical factor of adoptive cell therapy for solid tumors / 中国肿瘤生物治疗杂志

@#[Abstract] In recent years, tumor immunotherapy has developed rapidly, among which T-cell-based adoptive cell therapy has achieved certain clinical effect and become one of the most potential immunotherapeutics. T cell infiltration mainly includes rolling, adhesion, extravasation and chemotaxis etc. However, there are physical barriers, chemokine mismatch, vascular abnormalities, immunosuppressive microenvironment and other factors that limit the efficacy of adoptive cell therapy. The homing ability of T cells can be further improved by optimizing the chemokine receptor on the cell surface, inserting targeted peptide, improving the way of administration, and adopting combined treatment of radiotherapy, immune checkpoint blocker, tumor vaccine and bispecific antibody, etc. This review mainly summarizes the process of T cell infiltration, the influencing factors of T cell targeting tumor site and the relevant treatment strategies, as well as gives a prospection for future research.

Diagnosis and treatment experience of granulomatous cheilitis: case report and literature review / 口腔疾病防治

Objective@#To investigate the etiology, diagnosis and treatment of granulomatous cheilitis（GC）.@*Methods@# For a patient with recurrent granulomatous cheilitis for more than 1 year in whom no medical treatment was used, only systemic treatment of the teeth was performed, and its efficacy was observed. We also reviewed the relevant literature. @*Results@#The vermilion of the right lower lip of the patient was obviously swollen and soft. There was rebound and no pitting edema with palpation. A large dark red rash with local desquamation was observed on the skin over the right mandible. There were residual roots in tooth 35, 46, and 47, a porcelain bridge on 11-24, deep caries in 15, 16, 26, and 36, and many calculi in the whole mouth, and the gingival margin was obviously congested and swollen. Histopathological examination showed many lymphocytes infiltrated the superficial dermis, and granulation tissue, plasma cells and eosinophils infiltrated locally. The diagnosis was as follows: ① GC; ② 35, 46, and 47 residual roots; ③ 15, 16, 26, and 36 deep caries; ④ gingivitis. The treatment included extraction of 35, 46, and 47 residual roots, periodontal basic treatment, and fillings for 15, 16, 26, and 36. No drugs were administered except for 3 days after tooth extraction. After 5 weeks of treatment, the swelling of the lower lip and the skin rash completely disappeared. There was no recurrence in the follow-up observation at six months. Through a literature review and analysis, we found that GC may be related to various factors such as immunity, infection, and genetics. Local oral infections may be closely related to the incidence of GC.@*Conclusion @#Resolution of local oral infections is effective for the treatment of granulomatous cheilitis, and local oral infections may be closely related to the onset of granulomatous cheilitis. In the treatment of granulomatous cheilitis, attention should be paid to the systematic examination of the oral condition, and the treatment of suspected lesions in the oral cavity should begin in the early stages of treatment.

Mechanism and intervention of mucosal immune regulation based on "lung and large intestine being interior-exteriorly related" theory of traditional Chinese medicine / 浙江大学学报·医学版

The "lung and large intestine being interior-exteriorly related" is one of the classical theories in traditional Chinese medicine, which indicates a close correlation between the lung and large intestine in physiology and pathology, and plays a pivotal role in guiding the treatment of the lung and bowel diseases. Modern medicine has revealed some connections between the lung and large intestine in tissue origin and mucosal immunity, and preliminarily illuminated the material basis and possible regulatory mechanism of the theory. Recently, this theory has been applied to guide the treatment of refractory lung and intestine diseases such as COVID-19 and ulcerative colitis and has obtained reliable efficacy. Existing research results show that the anatomical homogeneity of lung and large intestine promotes the correlation between lung-bowel mucosal immunity, and mucosal immunity and migration and homing of innate lymphocytes are one of the physiological and pathological mechanisms for lung and large intestine to share. Under the guidance of this theory, Chinese medicines with heat-clearing and detoxifying or tonic effects are commonly used in the treatment of the lung and intestinal diseases by regulating lung-bowel mucosal immunity and they can be candidate drugs to treat lung/intestinal diseases simultaneously. However, the existing studies on immune regulation are mainly focused on the expression levels of sIgA and cytokines, as well as the changes in the number of immune cells such as innate lymphocytes and B lymphocytes. While the following aspects need further investigation: the airway/intestinal mucous hypersecretion, the functional changes of pulmonary and intestinal mucosal barrier immune cells, the dynamic process of lung/intestinal mucosal immune interaction, the intervention effect of local pulmonary/intestinal microecology, the correlation and biological basis between the heat-clearing and detoxifying effect and the tonic effect, and its regulation of pulmonary/intestinal mucosal immunity. In this paper, we try to analyze the internal relationship between lung and intestine related diseases from the point of view of the common mucosal immune system of lung and intestine, and summarize the characteristics and rules of traditional Chinese medicine compound and its active ingredients, which have regulatory effect on lung and intestine mucosal immune system, so as to further explain the theoretical connotation of "lung and large intestine being interior-exteriorly related" and provide reference for the research and development of drugs for related diseases.

Imaging study on the homing of regulatory T cells in humanized heterologous liver tissue transplan-tation mouse model / 中华核医学与分子影像杂志

Objective To explore the homing of DiR labeled regulatory T cells ( Tregs) in human-ized heterologous liver tissue transplantation mouse model. Methods The fluorescence intensities of Tregs labeled with different concentrations of DiR dye and different incubation times were measured, and the cell viability was measured by 3-( 4, 5-dimethylthiazol-2-yl )-5-( 3-carboxymethoxyphenyl )-2-( 4-sulfophenyl )-2H-tetrazolium ( MTS) assay to determine the optimal incubation time and dye concentration. The effect of DiR dye on the function and phenotype of Tregs was verified by flow cytometry. The xenogeneic liver tissue transplantation mouse model was constructed and the immune system was reconstituted. Small animal fluores-cence imaging was performed at different time points after infusion of Tregs. Immunohistochemistry analysis was used to analyze immune reconstitution and lymphocyte distribution in vivo. One-way analysis of variance and Dunnett-t test were used to analyze the data. Results With the increase of DiR concentration and incu-bation time, the fluorescence intensity of Tregs increased and gradually weakened after reaching the peak at 3 d. The cell viability of the 5. 00 μg/ml and 20. 00 μg/ml groups was significantly lower than that of the control group (culture medium) at various time points (F=120.142-182.025, t=9.969-19.329, all P<0. 05) . After incubation for 30 min and 60 min, the activity of Tregs was also significantly lower than that of the control group (F=21.826-301.968, t=6.897-40.016, all P<0.05). Tregs were finally co-incubated with DiR dye at a concentration of 2.50 μg/ml for 5 min, which was used further in vivo experiments. The flow cytometry showed that DiR dye did not affect the phenotype or the function of Tregs. The small animal fluorescence imaging showed that Tregs could locate in the graft area of mouse model. Immunohistochemical analysis showed that Tregs could improve lymphocyte infiltration induced by immune reconstitution. Conclu-sion After labeling Tregs with DiR dye, the distribution of Tregs can be directly observed by fluorescence imaging, which is a promising imaging method for Tregs tracer.

Mechanism of Allergic Asthma Pathogenesis by Protease Allergen / 한양의대학술지

Asthma is a complex immune mediated chronic inflammatory lung disease characterized by chronic inflammation of the airways, airway hyper-responsiveness and airway obstruction, and the prevalence of this disease has increased in recent years. It is well known that many features of allergic asthma are consequences of Th2 cell dominated immune responses against allergens, thus allergen specific Th2 cells play a critical role in the pathogenesis. In this review, we will discuss the properties of common indoor and outdoor allergens including house dust mite, fungus, pollen and cockroach, the activation and differentiation of naive CD4 T cells by protease allergens, how specific allergens modify host's immune system to mediate immune evasion, and regulation of homing receptor expression and trafficking of allergen specific Th2 cells. Lastly, we will also overview the general course of pathogenesis of allergic asthma and discuss prospects of development of novel immuno-therapies to asthma.

Stem Cells Expressing Homing Receptors Could be Expanded From Cryopreserved and Unselected Cord Blood

We assessed the cytokine combinations that are best for ex vivo expansion of cord blood (CB) and the increment for cell numbers of nucleated cells, as well as stem cells expressing homing receptors, by an ex vivo expansion of cryopreserved and unselected CB. Frozen leukocyte concentrates (LC) from CB were thawed and cultured at a concentration of 1x10(5)/mL in media supplemented with a combination of SCF (20 ng/mL)+TPO (50 ng/mL)+FL (50 ng/mL)+/-IL-6 (20 ng/mL)+/-G-CSF (20 ng/mL). After culturing for 14 days, the expansion folds of cell numbers were as follows: TNC 22.3+/-7.8~26.3+/-4.9, CFU-GM 4.7+/-5.1~11.7+/-2.6, CD34+CD38- cell 214.0+/-251.9~464.1+/-566.1, CD34+CXCR4+ cell 4384.5+/-1664.7~7087.2+/-4669.3, CD34+VLA4+ cell 1444.3+/-1264.0~2074.9+/-1537.0, CD34+VLA5+ cell 86.2+/-50.9~ 113.2+/-57.1. These results revealed that the number of stem cells expressing homing receptors could be increased by an ex vivo expansion of cryopreserved and unselected CB using 3 cytokines (SCF, TPO, FL) only. Further in vivo studies regarding the engraftment after expansion of the nucleated cells, as well as the stem cells expressing homing receptors will be required.

Effects of ovulation induction on expression of integrins ?_4?_1 in endometrium / 中华妇产科杂志

Objective To study the effect of clomiphene citrate (CC) and human menopausal gonadotropin (hMG) on the expression of integrins ? 4? 1 during implantation window in endometrium. Methods Endometrium integrin ? 4? 1 expression was detected by immunohistochemistry method in the mid secretory phase of 48 normal natural cycles. CC+hCG or CC+hMG+hCG cycles in 30 polycystic ovary syndrom (PCOS) patients and 48 normal women. Results The expression of endometrial integrin ? 4? 1 was stronger in the natural cycls than those of ovulation induction cycles with CC+hCG or CC+hMG+hCG. So was the pregnancy cycles as compared with the non pregnant cycles. Conclusion The endometrial receptivity in the min luteal phase and pregnant rate declined during ovulation induction by CC+hCG or CC+hMG+hCG in either normal women or PCOS patients.

The effect of lymphocyte homing to intestine and adhension molecules to intestinal immunologic barrier / 肠外与肠内营养

Intestinal immunologic barrier plays an important role in preventing the bacterium and endotoxin.Lymphocyte homing to the intestine is one of the normal intestinal immunologic functions,and has the theoretical significance and clinical value for the balance of intestinal immunologic barrier.The basic and clinical researches of lymphocyte homing to the intestine are reviewed.

Immunohistochemical Study of Skin homing T Lymphocytes in Psoriasis Vulgaris / 中华皮肤科杂志

Objective To investigate the role of skin homing T lymphocytes in the development of psoriasis vulgaris(PV). Methods Indirect immunofluorescent double staining technique was employed to study the expression of infiltrating skin homing T lymphocytes in normal, uninvolved perilesional and lesional psoriatic skin in different stages (progressing, stable or regressing) and in normal human skin. Results ①Expression of cutaneous lymphocyte associated antigen (CLA) was found in the majority of CD3+T lymphocytes in normal human skin and in lesions of PV, and CD45RO phenotype was expressed in almost all CLA+T lymphocytes. ②In psoriatic lesions, the number of CD4+CLA+and CD8+CLA+cells was higher in progressive stage than that in stable stage(P