New approaches to understanding the immune response to vaccination and infection

The immune system is a network of specialized cell types and tissues that communicates via cytokines and direct contact, to orchestrate specific types of defensive responses. Until recently, we could only study immune responses in a piecemeal, highly focused fashion, on major components like antibodies to the pathogen. But recent advances in technology and in our understanding of the many components of the system, innate and adaptive, have made possible a broader approach, where both the multiple responding cells and cytokines in the blood are measured. This systems immunology approach to a vaccine response or an infection gives us a more holistic picture of the different parts of the immune system that are mobilized and should allow us a much better understanding of the pathways and mechanisms of such responses, as well as to predict vaccine efficacy in different populations well in advance of efficacy studies. Here we summarize the different technologies and methods and discuss how they can inform us about the differences between diseases and vaccines, and how they can greatly accelerate vaccine development.     

Internet activity as a proxy for vaccination compliance

Tracking the progress of vaccination campaigns is a challenging and important public health need. Examining a recent Polio outbreak in the Middle East, we show that novel methods utilizing online search trends have great potential to provide a real-time, reliable proxy for vaccination rates over space and time.     

Evidence for induction of humoral and cytotoxic immune responses against devil facial tumor disease cells in Tasmanian devils (Sarcophilus harrisii) immunized with killed cell preparations

Tasmanian devils (Sarcophilus harrisii) risk extinction from a contagious cancer, devil facial tumour disease (DFTD) in which the infectious agent is the tumor cell itself. Because devils are unable to produce an immune response against the tumor cells no devil has survived ‘infection’. To promote an immune response we immunized healthy devils with killed DFTD tumor cells in the presence of adjuvants. Immune responses, including cytotoxicity and antibody production, were detected in five of the six devils. The incorporation of adjuvants that act via toll like receptors may provide additional signals to break ‘immunological ignorance’. One of these devils was protected against a challenge with viable DFTD cells. This was a short-term protection as re-challenge one year later resulted in tumor growth. These results suggest that Tasmanian devils can generate immune responses against DFTD cells. With further optimization of immune stimulation it should be possible to protect Tasmanian devils against DFTD with an injectable vaccine.     

What has happened in the last 50 years in immunology

Fifty years ago, in 1964, our understanding of the immune system was very rudimentary. Gell and Coombs had just described classes of hypersensitivity reactions, and Bruton had described and commenced immunoglobulin replacement in agammaglobulinaemia. The distinction between T and B cells was not identified and characterised until the 1960s and 1970s. This was followed by increasing recognition of T and B cell collaboration in immune responses and identification of significant immunodeficiencies. CD4 and CD8 T cells were only recognised in the 1970s and 1980s. We now know of five CD4 subsets; dysfunction of each is associated with different disorders. By 2014, advances in technology have enabled identification of the genetic basis of over 240 primary immunodeficiencies. Research into the gut microbiome and vitamin D holds promise for the understanding, treatment and prevention of autoimmune and allergic diseases. Immunoglobulin preparations for the treatment of antibody deficiencies improved with the development of preparations for intravenous then subcutaneous administration, giving patients choice and the ability for home‐based treatment, especially if experiencing infusion associated adverse effects. Newborn screening for severe combined immunodeficiency is a reality. Improvements in haemopoietic stem cell transplantation and now gene therapy, albeit still only available in the research setting, are improving long‐term survival in primary immunodeficiencies. Biologic therapeutic agents are improving the control of autoimmune disease but potentially leading to secondary immunodeficiency, increasing the risk of opportunistic infection and malignancy. It is an exciting time.     

Association of toll-like receptor 10 polymorphisms with pediatric pneumococcal meningitis

We aimed to investigate whether the gene polymorphisms of TLR10 were associated with risk and severity of pneumococcal meningitis (PM) and serum cytokine levels in children. Three single nucleotide polymorphisms (SNPs) of TLR10 rs4129009 (2676A > G), rs10004195 (1018T > A) and rs11466617 (40735A > G) were studied in 95 laboratory-confirmed PM pediatric patients and 330 healthy controls by PCR-based sequencing. Ten serum cytokines were determined by multiplex immunoassay. The frequency of variant haplotype GAG of TLR10 was significantly lower in patients than controls (11.3% vs 33.3%, p < 0.001), although frequencies of the genotypes and alleles of the three SNPs did not differ between patients and controls. Frequency of variant haplotype GAG was significantly lower in patients who had CSF protein >1000 mg/L than those who had CSF protein ≤1000 mg/L (3.50% vs 32.4%, p < 0.001). Moreover, higher frequency of the haplotype GAG was found in patients who had higher levels of inflammatory cytokines such as IFN-γ, TNF-α and IL-1β. Our finding suggested that the variant haplotype GAG in TLR10 is associated with decreased risk of PM in Chinese children.     

Melanoma brain metastases: Biological basis and novel therapeutic strategies

The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.     

加味葛根芩连汤联合常规治疗对重度湿热型溃疡性结肠炎患者的临床疗效

目的考察加味葛根芩连汤联合常规治疗对重度湿热型溃疡性结肠炎患者的临床疗效。方法82例患者随机分为对照组和观察组,每组41例,对照组给予常规治疗(美沙拉嗪、氢化可的松琥珀酸钠),观察组在对照组基础上加用加味葛根芩连汤,疗程4周。检测症状评分、中医证候疗效、肠镜Baron评分、膜屏障功能指标(HIF⁃1α、DAO、D⁃LA)、血清促炎因子(IL⁃2、IL⁃6、TNF⁃α、IFN⁃γ、CRP)、血清抗炎因子(IL⁃4、IL⁃10、IL⁃13)、免疫功能指标(CD3+、CD4+、CD8+、CD4+/CD8+、NK细胞)、凝血功能指标(FIB、APTT、PLT)、不良反应发生率变化。结果观察组总有效率较对照组升高(P<0.05)。治疗后,观察组症状评分、肠镜Baron评分、膜屏障功能指标、血清促炎因子、CD8+、FIB、PLT、不良反应发生率较对照组降低(P<0.05),血清抗炎因子、CD3+、CD4+、CD4+/CD8+、NK细胞、APTT升高(P<0.05)。结论加味葛根芩连汤联合常规治疗能有效缓解重度湿热型溃疡性结肠炎患者临床症状,保护肠黏膜,降低不良反应,其机制可能与抑制促炎因子分泌、促进抗炎因子分泌、激活免疫功能、改善凝血功能有关。     

一测多评法同时测定艾纳香油中5种成分

目的建立一测多评法同时测定艾纳香Blumea balsamifera(L.)DC.油中β⁃蒎烯、β⁃石竹烯、樟脑、α⁃石竹烯和龙脑5种成分的含有量。方法艾纳香油乙酸乙酯提取物的分析采用PEG⁃20 M柱(30 m×0.32 mm,1.0μm);程序升温;载气为高纯氮气(99.999%);FID检测器温度240℃,进样口温度240℃。以龙脑为内标,计算其他4种成分的相对校正因子,再测定其含有量。结果蒎烯、β⁃石竹烯、樟脑、α⁃石竹烯和龙脑分别在1.49~59.5μg/mL(r=0.9996)、2.22~88.8μg/mL(r=0.9996)、6.48~259μg/mL(r=0.9997)、3.64~146μg/mL(r=0.9991)和16.4~656μg/mL(r=0.9998)范围内线性关系良好,平均加样回收率(RSD)分别为97.4%(0.9%)、99.0%(1.3%)、98.9%(0.9%)、97.6%(0.9%)和99.7%(1.0%)。一测多评法所得结果接近于外标法。结论该方法准确稳定,重复性好,可用于艾纳香油的质量控制。     

Tracking the immune response with single-cell genomics

The immune system is composed of a diverse array of cell types, each with a specialized role in orchestrating the immune response to pathogens or cancer. Even within a single cell ‘type,’ individual cells can access a wide spectrum of differentiation and activation states, which reflect the physiological response of each cell to the tissue environment and immune stimuli. Thus, the cellular diversity of the immune system is inherently quite complex and understanding this complexity has greatly benefited from technologies that measure immune responses at single-cell resolution, in addition to the systems-level response as a whole. In this Commentary, we focus on recent work at the interface of immunology and single-cell genomics and highlight advances in technologies and their application to immune cells. In particular, we highlight recent single-cell genomic profiling studies of T cells, since somatic rearrangements in the T cell receptor (TCR) loci enable the tracking of clonal T cell responses through space and time. Finally, we discuss opportunities for future use of these technologies in understanding vaccination and the basis for effective vaccine-induced immunity.