Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity

The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases. Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40–OX40L interaction. Despite this progress, many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered. In this review we summarize the impact of the OX40–OX40L interaction on T cell subsets, including Th1, Th2, Th9, Th17, Th22, Treg, Tfh, and CD8⁺ T cells, to gain a comprehensive understanding of anti-OX40 mAb-based therapies. The potential therapeutic application of the OX40–OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed; OX40–OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases. We also explore the rationale of targeting OX40–OX40L interactions in cancer immunotherapy. Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells. When combined with other therapeutic treatments, such as anti-PD-1 or anti-CTLA-4 blockade, cytokines, chemotherapy, or radiotherapy, the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced. These data collectively suggest great potential for OX40-mediated therapies.     

Applications of geospatial analyses in health research among homeless people: A systematic scoping review of available evidence

BackgroundUnequal housing access resulted in more than 150 million homeless people worldwide, with millions more expected to be added every year due to the ongoing climate-related crises. Homeless population has a counterproductive effect on the social, psychological integration efforts by the community and exposure to other severe health-related issues. Geographic Information Systems (GIS) have long been applied in urban planning and policy, housing and homelessness, and health-related research.MethodsWe used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to systematically review 24 articles collected from multiple databases (n = 10) that focused on health-related issues among homeless people and used geospatial analysis techniques in their research.ResultsOur findings indicated a geographic clustering of case study locations– 26 out of the 31 case study sites are from the USA and Canada. Studies used spatial analysis techniques to identify hotspots, clusters and patterns of patient location and population distribution. Studies also reported relationships among the location of homeless shelters and substance use, discarded needles, different infectious and non-infectious disease clusters.ConclusionMost studies were restricted in analyzing and visualizing the patterns and disease clusters; however, geospatial analyses techniques are useful and offer diverse techniques for a more sophisticated understanding of the spatial characteristics of the health issues among homeless people. Better integration of GIS in health research among the homeless would help formulate sensible policies to counter health inequities among this vulnerable population group.     

HBV患者血清YKL-40、CA19-9、GP73水平与其病情相关性

目的 分析HBV患者YKL-40、CA19-9、GP73水平差异及与患者病情轻重程度的相关性,探讨HBV患者病情的判定指标。方法 选取2015年5月—2018年5月收治的100例HBV患者,其中慢性HBV感染组40例、慢性乙型肝炎组36例、HBV相关肝硬化组24例,同期选择我院健康体检的健康者50例作为健康对照组;检测患者血中YKL-40、CA19-9、GP73水平;分析HBV感染患者血清YKL-40、CA19-9、GP73水平与病情轻重程度的相关性。结果 慢性HBV感染、慢性乙型肝炎及HBV相关肝硬化患者血中YKL-40水平分别为（36.38±4.19）ng/mL 、（49.02±4.32）ng/mL、（65.14±5.21）ng/mL ,CA19-9分别为（12.03±1.03）KU/L、（13.84±0.98）KU/L、（16.94±0.81）KU/L,GP73分别为（47.22±5.38）ng/mL 、（98.53±10.24）ng/mL 、（229.85±12.19）ng/mL,均明显高于对照组的（28.19±3.27）ng/mL 、（7.34±0.92）KU/L 、（30.93±3.89）ng/mL,均P=0.000 0。随着慢性HBV感染者、慢性乙型肝炎患者和不同HBV相关肝硬化患者肝脏炎症及纤维化程度加重,患者血中YKL-40、CA19-9和GP73也随之显著增加,均P=0.000 0;YKL-40、CA19-9和GP73均是影响HBV感染患者体内炎症坏死及肝脏纤维化的独立性影响因素,差异有统计学意义（P<0.05）。结论 HBV感染患者血清中YKL-40、CA19-9、GP73水平是HBV感染患者病情轻重程度的独立性影响因素。     

Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

BackgroundDiffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.MethodsSyngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.ResultsExpression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.ConclusionsVirus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.     

Angiodysplasia as the cause of massive lower gastrointestinal hemorrhage in a young adult

PURPOSE: This study was undertaken to clarify the importance of bleeding vascular ectasia of the colon as the etiology of massive lower gastrointestinal hemorrhage in patients 40 years of age or younger. METHODS: An otherwise healthy 21-year-old male was admitted to a tertiary medical center with massive lower gastrointestinal hemorrhage. Technetium-labeled red blood cell scan, selective visceral angiography, and colonoscopy identified the source of bleeding as vascular abnormality of the descending colon. Segmental colonic resection was performed. RESULTS: Histologic review of the specimen demonstrated a vascular ectasia. The patient recovered uneventfully and has had no further stigmata of hemorrhage. A review of the literature was undertaken to make clear the significance of vascular ectasia as the source for massive colonic hemorrhage in the young adult. CONCLUSION: This is the first report that documents histologically a vascular ectasia as the source of massive lower gastrointestinal hemorrhage in an otherwise healthy patient less than 40 years of age. Vascular ectasia is an uncommon cause of lower gastrointestinal hemorrhage in the young adult.The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program sponsored this report #84-16-1968-532, as required by HSETCINST 6000.41A. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.     

Hyper-IgM syndrome with CHARGE association

A girl with coloboma of the iris, sensorineural deafness, growth delay, distinctive face, and cranial nerve dysfunction was diagnosed of CHARGE association in the first year of life. She presented with repeated otitis. At 3 yr of age, the patient suffered a septicemia ( Streptococcus pneumoniae , Corynebacterium sp.). The immunoglobulin G (IgG) and IgA serum levels were decreased, IgM increased and cellular immunity parameters were normal, supporting the diagnosis of hyper-IgM (HIM) syndrome. The sequence of CD40 ligand and cytidine deaminase genes were normal. From then on, she was receiving immunoglobulin intravenously with an excellent outcome . Here, we report the first case of CHARGE association and HIM syndrome in the same patient. Although the cause could not be identified, a non-random link is likely.     

LHRH-PE40识别结肠癌细胞膜表面蛋白的研究

目的探讨人结肠癌细胞系Lovo及人白血病细胞系Jurket细胞膜表面蛋白能否识别LHRH-PE40及是否存在竞争性抑制。方法将结肠癌细胞系Lovo及白血病细胞系Jurket制备成细胞膜,利用125I标记的LHRH-PE40与两种细胞膜进行放射性配基分析,与LHRH进行竞争结合分析。结果人结肠癌细胞系Lovo的结合竞争符合特异性配基-受体结合、竞争;而白血病细胞系Jurket未见配基-受体特异性结合。其中LHRH-PE40与Lovo细胞的亲和力:Kd=10·6±2·33nmol/L,容量Bmax=345±7·59pmol/mg。结论LHRH是结肠癌免疫治疗的有效靶点,LHRH-PE40对过度表达LHRH受体的结肠癌具有特异性杀伤作用,而对无LHRH表达的肿瘤无杀伤作用,对于药物的临床应用有着指导意义。     

Development of intestinal epithelial cell lines using a transgenic mouse

The epithelial cells of the colonic mucosa of the animal have proved impossible to culture using standard tissue culture techniques. Immortalization of adult colonic epithelial cells has been unsuccessful due to the lack of DNA synthesis in these cells once they are isolated from the tissue. Recently an unique transgenic mouse bearing a temperature sensitive mutant of the known immortalizing gene, SV40 large T has become available. The advantage of this mouse is that the SV40 large T gene is expressed in every cell. Active immortalizing protein is produced in each cell at the permissive temperature. We have used colonic mucosa from these mice to initiate cultures of epithelial cells from the colon of adult mice. The cells grow readily at the permissive temperature but die within 7 days at the non-permissive temperature. The methods used to develop these cultures are described.     

胃癌根治术病人围术期异体输血后外周血单核细胞CD40L表达的变化

目的 研究胃癌根治术病人围手术期异体输血外周血单核细胞(PBMCs)白细胞分化抗原40配体(CD40L)表达的变化。方法 胃癌根治术病人30例,随机分为3组,每组10例。A组围术期不输血,B组围术期输入去白细胞的全血,C组围术期输入异体全血。另选10例健康人作为对照。分别在手术前、术后2、5、10 d采外周静脉血5 ml,用Ficoll分离液梯度离心法分离出PBMCs和血浆,将PBMCs置于自身血浆环境中,并在植物血凝素(PHA,20 mg/L)的刺激下进行培养,48 h后收获细胞,用流式细胞术检测CD40L表达。结果 健康人外周血未受PHA刺激时检测不到CD40L的表达,经PHA刺激后CD40L 细胞占CD4 T细胞的百分数为1.7％±0.4％,与三组胃癌病人术前比较差异无显著性(P>0.05)。与术前比较,B组术后2 d PBMCs CD40L表达升高(P<0.05),C组术后各时点升高(P<0.05);与A组比较,B组术后2 d升高(P<0.05),C组术后各时点升高(P<0.05);与B组比较,C组术后各时点升高(P<0.05)。结论 围手术期异体输血可造成免疫抑制,输异体血后CD40L表达增加,且输全血比输去白细胞的全血更明显。围手术期成分输血优于输注全血。