PubMed | University of Bristol, University of Cardiff, University of Warwick and QIMR
Type: | Journal: The Journal of biological chemistry | Year: 2016
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell cross-reactivity, with important implications for pathogen surveillance, autoimmunity and transplant rejection.
News Article | November 7, 2016
BEIJING and LA JOLLA, Calif., Nov 7, 2016 /PRNewswire/ -- Yisheng Biopharma Co., Ltd. ("Yisheng Biopharma"), a biopharmaceutical company focusing on research, development, manufacturing, sales and marketing of vaccine products, today announced that it has entered into a collaboration with The Scripps Research Institute ("TSRI") to test a new generation of AIDS vaccine based on novel gp140 trimers and self-assembling nanoparticles designed by TSRI scientists and Toll-Like Receptor 3 (TLR3) agonist adjuvant technology ("PIKA") developed by the company. The cooperative research partnership represents a new opportunity for both organizations to create more effective and safe vaccine products against HIV infection. Under the terms of the agreement, the scientists at TSRI will evaluate the potential of PIKA adjuvant for AIDS vaccine candidates. The PIKA adjuvant is a proprietary technology developed by Yisheng Biopharma, named as part of "National Key Medicine Innovation" in 2013 by the National Ministry of Science and Technology of China. Most recently Yisheng completed Phase II and Phase I clinical studies of PIKA based rabies and hepatitis B vaccines, respectively, which exhibited promising efficacy and safety in human subjects. "TSRI has gained a great deal of expertise in AIDS research which lays the groundwork in revolutionizing vaccine design strategy," commented Assistant Professor Jiang Zhu at TSRI. "TLR-3 agonists such as PIKA adjuvant are known to enhance immune responses. When used together with highly optimized HIV vaccine immunogens, PIKA could activate innate immune signaling and induce a more robust immune response that confers protection against HIV infection. We look forward to working with researchers at Yisheng to develop a more powerful AIDS vaccine." "The partnership with TSRI is critical to our long-term vision in advancing vaccine development. We're thrilled to work alongside TSRI's world-class faculty and bring Yisheng's capabilities and focus to bear in creating new medicines into the future. We are very pleased to join forces with TSRI in exploring a more effective vaccine against AIDS, which remains a significant unmet medical need. Our PIKA adjuvant has exhibited broad potential in preclinical and clinical investigations against rabies, HIV, Hepatitis-B, influenza, tuberculosis, and other viruses, which could significantly change the clinical practice paradigms against many human and animal virus infections. We are looking forward to updating the progress on these fronts in due course," stated Mr. Yi Zhang, the Chairman of Yisheng Biopharma and the project leader of PIKA adjuvant technology. Mr. Zhang finally commented, "We are grateful to our research collaborators worldwide for their continuous support of PIKA adjuvant technology and vaccine development over the years, including The Pasteur Institute, the US NIH, the United States Army Medical Research Institute of Infectious Diseases, Chinese Center For Disease Control And Prevention (China CDC), China National Institutes For Food and Drug Control, DSO National Laboratories Singapore, Chinese Academy of Sciences, Australia QIMR, Sun Yat-Sen University of China, Aeras Pharmaceutical of the US, and Academy of Military Sciences of China." PIKA adjuvant technology is a proprietary technology developed in-house at Yisheng Biopharma. The adjuvant is a double- stranded RNA, which acts as a toll-like receptor-3 (TLR-3) ligand to the activation of the innate immune cells, such as dendritic cells, macrophages and NK cells. PIKA adjuvant is formulated as a component of vaccine candidates. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists - including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine - work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu. About Yisheng Biopharma Co., Ltd. Yisheng Biopharma Co., Ltd. is a biopharmaceutical company headquartered in Beijing, China, focusing on the research, development, manufacturing and sales and marketing of immunological and vaccine products, with approximately 1,000 employees in China, the USA and Singapore. For more information, see www.yishengbio.com
PubMed | QIMR
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016
9683 Background: More than 100 variables have been described to predict prognosis in breast cancer but only maximum tumour size (T), histological grade, nodal status, ER and HER-2 are routinely incorporated into clinical practice. In this study both classic histological features and novel biomarkers using immunohistochemistry (IHC) were evaluated to assess overall survival.Formalin fixed paraffin embedded tissue was collected from 414 breast cancer patients with invasive ductal carcinoma. 247 patients were node negative. Median follow-up was 110 months (Range 1-148 months). Routine histological parameters were assessed and a number of antigens including ER, PR, HER-2, p53, Ki67 and microvessel density were evaluated using IHC. ER, PR, HER-2 and p53 were assessed semiquantitatively using the Quickscore method. Microvessel density was counted over a 200x field and adjusted to mmWith univariate analysis, grade (p <0.001), nodal status (p <0.001), tumour volume (p <0.01), HER-2 (p = 0.006), Ki67 (p <0.001), mitotic rate (p <0.001) and T (p <0.001) were statistically significant. For node negative patients grade (p = 0.02), tumour volume (p = 0.03) and mitotic rate (p = 0.009) were significant. Using multivariate analysis, mitotic rate (p = 0.0005) and tumour volume (p <0.001) predicted nodal involvement, and grade (p = 0.002), nodal status (p = 0.001) and T (p <0.001) predicted overall survival.This analysis validates the current staging system. Additional IHC markers failed to predict overall survival when standard histological features were utilised. Mitotic rate and tumour volume were independent predictors of nodal metastases. Tumour volume estimation may be superior to T in predicting nodal metastases and requires further evaluation to determine its potential role in staging. No significant financial relationships to disclose.