Regulatory T cells for tolerance

Regulatory T cells (Tregs) are critical mediators of immune homeostasis and hold significant promise in the quest for transplantation tolerance. Progress has now reached a critical threshold as techniques for production of clinical therapies are optimised and Phase I/II clinical trials are in full swing. Initial safety and efficacy data are being reported, with trials assessing a number of different strategies for the introduction of Treg therapy. It is now more crucial than ever to elucidate further the function and behaviour of Tregs in vivo and ensure safe delivery. This review will discuss the current state of the art and future directions in Treg therapy.     

A New Model for Catalyzing Translational Science: The Early Stage Investigator Mentored Research Scholar Program in HIV Vaccines

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large‐scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.     

Measuring T-cell responses against LCV and CMV in cynomolgus macaques using ELISPOT: Potential application to non-clinical testing of immunomodulatory therapeutics

Abstract

A number of immunomodulatory therapeutics increase the risk of disease associated with latent herpesviruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), a member of the lymphocryptovirus (LCV) family that infects humans. The diseases associated with loss of immunity to these viruses can have major impacts on patients as well as on the commercial viability of the immunomodulatory therapeutics. In an effort to develop non-clinical methods for measuring effects on anti-viral immunity, we have developed an interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) assay to quantify the number of CMV or LCV-reactive T-cells in peripheral blood of cynomolgus macaques. After optimization of various parameters, the IFN-γ ELISPOT assay was characterized for specificity, intra-assay, monkey-to-monkey, and longitudinal variability and sensitivity to immunosuppression. The results show that nearly all animals have detectable responses against both CMV and LCV and responses were derived from T-cells specific to the virus of interest. Analyses of variability show assay reproducibility (≤23% CV), and that variability over time in anti-viral responses in individual animals (larger for LCV than for CMV) was ～2-fold in most animals over a 3-month time period, which is predicted to allow for detection of drug-induced changes when using group sizes typical of non-clinical studies. In addition, the IFN-γ ELISPOT assay was capable of detecting decreases in the numbers of CMV and LCV reactive T-cells induced by immunosuppressive drugs in vitro. This assay may allow for non-clinical assessment of the effects of immunomodulatory therapeutics on anti-viral T-cell immunity in monkeys, and may help determine if therapeutics increase the risk of reactivating latent viral infections.     

Quality-of-life in patients with Dercum's disease—before and after liposuction

Abstract

Dercum's disease is characterised by obesity, pronounced pain in the adipose tissue, and a number of associated symptoms. Liposuction has been suggested as a treatment. However, the effect on quality-of-life after liposuction in Dercum's disease has never been investigated. The objective of this study was to examine the quality-of-life in Dercum's disease before and after liposuction. A total of 114 women fulfilling the clinical criteria of Dercum's disease were included. Of the 114 women, 53 were operated on with liposuction and 61 were Dercum controls. In addition, 41 obese healthy women operated on with abdominoplasty were recruited as controls. Health-related quality-of-life (HRQoL) was measured with the Nottingham Health Profile (NHP) and the Psychological General Well-Being index (PGWB). The Dercum group had lower HRQoL than the abdominoplasty controls. After liposuction, a slight improvement could be seen in HRQoL in the operated patients compared with preoperatively, but it did not become as high as in the abdominoplasty patients. In conclusion, the findings could suggest that liposuction improves the quality-of-life slightly in Dercum's disease. Nonetheless, the causality is unclear and the improvement is not big enough to warrant operation.     

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.     

fMRI of Cocaine Self-Administration in Macaques Reveals Functional Inhibition of Basal Ganglia

Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion.     

颅内肿瘤患者术前生存质量及其影响因素研究

目的探讨颅内肿瘤患者术前生存质量及其影响因素。方法采用诺丁汉健康调查表(Nottinghamhealthpoofite,NHP)对89例CT、MRI诊断颅内肿瘤患者的生存质量进行评价研究。结果颅内肿瘤患者术前生存质量的损坏程度与颅内肿瘤的大小之间没有线性关系,颅内肿瘤的体积>25ml比≤25ml者生存质量差,颅内肿瘤位于右侧半球的患者比位于左侧半球的患者生存质量要差,肿瘤位于幕下者比幕上者生存质量更差,恶性程度高的颅内肿瘤患者显示了较差的生存质量。结论对颅内肿瘤患者术前生存质量进行估计评价时,不仅要考虑社会、医学因素,还应考虑到肿瘤的位置,大小和恶性程度对术前生存质量的影响。     

多发伤患者创伤后生活质量的研究

目的通过对ICU救治存活的多发伤患者定期随访，对其出院1年后的生理和残疾情况以及日常生活和社会活动能力进行调查，对多发伤患者伤后的生活质量进行评估，研究创伤情况与伤后生活质量之间的关系。方法采用创伤严重程度评分（ISS），格拉斯哥预后评分（GOS），格拉斯哥昏迷评分（GCS），诺丁汉健康量表（NHP）评分法对人选者进行统计分析，研究其创伤后的生理状态，残疾情况和生活质量与创伤严重程度的相关性。结果选取经抢救存活的60例患者，对其中35例来院复诊或经过电话联系的患者进行了随访。大多数患者在出院1年后生活质量受到一定的影响，其中20例恢复工作，4例存在一定程度上的残疾，无法生活自理。结论严重多发伤患者创伤后经救治成活者，总体生活质量受到一定的影响。患者的ISS及头部的创伤情况与创伤后生活质量有关。