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Literature Highlights

                     
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CD8+ T Cell Responses restricted by MHC class II exist in human HIV Infection: a role in infection control?
By QUENTIN HAAS
Ranasinghe and colleagues report about the capacity of CD8+ T cells to elicit a HLA class II restricted CD8+ T cells immune response in chronic human HIV infection. These results challenge the paradigm concerning CD8+ T cells recognition and restriction, and may play a key role in the development of future T cell based vaccine and immunotherapy of viral infections.
Immunity, October 18 (2016)
 
Antimalarial treatment doesn’t affect cancer’s immune answer
By QUENTIN HAAS
Antimalarial treatment as well as inhibitors of apoptosis have shown no impact on the efficiency of the adaptive immune system to produce an anti-tumor response. These data suggest that the combination of these treatments with anti-tumor therapies is possible, and might become useful in various clinical contexts.
Journal of clinical investigations, October 24 (2016)
 
Romosozumab treatment beneficially affects osteoporosis.
By QUENTIN HAAS
In this large-scaled study, the beneficial effects of the monoclonal antibody to sclerostin (so-called Romosozumab) on osteoporosis in postmenopausal woman was tested over a period of 2 years. The data showed a beneficial effect of the treatment over the placebo group, with a diminished number of vertebral fractures after 12 and 24 months.
The New-England Journal of Medicine, October 10 (2016).
 
Pembrolizumab treatment in NSCLC patients: a phase 3 trial results.
By QUENTIN HAAS
In this open-label, phase 3 trial, the effects of the Pembrolizumab, a monoclonal antibody against PD-1, was assessed on advanced untreated NSCLC patients. The results not only showed an ameliorated survival rate, but also a diminished number of adverse events compared to platinum-based chemotherapy.
The New-England Journal of Medicine, October 9 (2016).
 
Venetoclax resistance in activated CLL cells can be overcome by Kinase inhibitors.
By QUENTIN HAAS
Venetoclax is a promising treatment developed against chronic lymphocytic leukemia (CLL) that inhibits Bcl2 and helps to induce apoptosis. However, resistance to the treatment was reported. In this study, Opperman et al. developed a model of culture which mimic microenvironment of tumors, and therefore increased pertinence of the answer observed from cancer cells under treatments. Their approach permitted the discovery of a drug combination that overcomes CLL resistance to Venetoclax, and increased the knowledge about the impact of the microenvironment on treatment response.
Blood, September 19 (2016).
 
Replication-defective virus vaccine: positive outcomes in human!
By QUENTIN HAAS
Wang and colleagues modified a human cytomegalovirus (HCMV) so that its replication machinery would be defective and therefore could be used as vaccination tool to enhance the immunogenicity of the treatment. The results of their study show an important and safe immune answer to the treatment. Thus, the utilization of such replication-defective virus in vaccines is proven possible and might open a wide field of possibilities in order to create a new generation of treatments against viruses.
Science translational medicine, October 26 (2016).
 
Vaccination by bolus dose: old fashioned?
By QUENTIN HAAS
Since its discovery, vaccine has been administrated at once, injecting abolus dose in the organism. As a natural infection is usually from a longer duration with a different pattern of presence of the antigen, an assay was developed to mimic this more natural kinetics over a 1-2 weeks’ vaccination process during germinal center induction. The resulting enhanced GC B-cell differentiation and antigen-specific antibody production may influence the posology of vaccines in the nearest future.
PNAS, October 3 (2016).
 
Innate and adaptive immune response collaboration to treat cancer.
By QUENTIN HAAS
Most of immune treatments of cancer have shown a large variety of limitations, resulting in a modest antitumor efficacy when used individually. By combining treatments such as tumor-antigen-specific antibody, anti PD-1 and amphiphile–vaccine, the outcome on the eradication of cancer in mice was promising. Despite the complexity of defining optimal dosing levels and schedules for each component, the possibilities of treatment using several combinations of agents are limitless and promising.
Nature Medicine, October 24 (2016)

Adoptive T Cell-Transfer in the Treatment of B Cell Malignancies
By CHRISTOPH SCHNEIDER
Ramos CAand colleagues report about the generation of chimeric antigen receptors (CARs), which are specific for the κ-light chain of the B cell receptor. CAR T cells therefore only target κ-light chain expressing B cells, which are characteristic for various B cell malignancies. The published phase-I study indicated feasibility and the potential of such CAR T cells to lead to complete clinical responses.
Journal of Clinical Investigation, June 6 (2016)
 
A STING into the Cancer’s Heart
By CHRISTOPH SCHNEIDER
Stimulator of interferon genes, short STING, plays central roles in detecting misplaced DNA. Emily Curran and colleagues activated the STING pathway, using the antagonist DMXAA, in case of acute myeloid leukemia (AML) in mouse models. The team observed pronounced induction of interferons and finally a significant increase in the overall survival in two different mouse models of AML, rendering STING to a promising pharmacological target.
Cell Reports,June 14 (2016)
 
Sepsis = False Alarm?
By CHRISTOPH SCHNEIDER
If bacteria enter the blood stream, a life-threatening condition called sepsis, characterized by a massive immune response and cell death, can occur. For decades, the reasons for these events have remained obscure. Vanaja S and colleagues now identified outer membrane vesicles (OMVs), produced by bacteria, which deliver lipopolysaccharides (LPS) to the cytosol of host cells. In the cytosol, the released LPS is sensed by caspase-11, which activates cascades leading to inflammation and cell death – a reaction which only should take place, when the bacteria it-self is in the intracellular compartment. Targeting OMV-pathways might therefore be reasonable therapeutic or preventative approaches.
Cell, May 19 (2016)
 
Promising Ebola-Vaccine
By CHRISTOPH SCHNEIDER
In 2014, the outbreak of Ebola in various African countries was declared as a public health emergency of international concern. Selidji Agnandji and colleagues recently tested a vaccine-approach using replicating-competent stomatitis viruses, which express an Ebola-virus glycoprotein. While no serious side effects were reported in a cohort of 158 volunteers, further analysis revealed promising immune responses even after a single dose, rendering the vaccine to an interesting candidate for future studies.
New England Journal of Medicine, April 28 (2016)
 
RNAi: A Potential Antibiotics-Substitution Approach
By CHRISTOPH SCHNEIDER
For decades, antibiotics have been the gold standard in fighting bacterial infections. Due to emerging resistances, novel treatment approaches are needed more than ever. Manoj Puthia and colleagues report about effective fighting of bacterial infections by boosting the innate immune system. Targeting the transfection factor interferon regulatory factor 7 (IRF-7), protected mice against infections. RNAi-based inhibition of IRF-7 could be a valuable approach to treat bacterial infections without the use of classical antibiotics.
Science Translational Medicine, April 27 (2016)
 
Treatment-Possibilities for Inflammatory Conditions!
By CHRISTOPH SCHNEIDER
Neutrophils are major effector cells in acute inflammatory responses. During apoptosis or necrosis, dying neutrophils release a variety of antimicrobial peptides, including the human neutrophil peptide 1 (HNP1). Matthew Brook and colleagues show, that HNP1 effectively inhibits protein translation in macrophages, thereby limiting inflammatory responses. Taking advantage of this newly gained knowledge, future peptide-based therapeutic could act as an anti-inflammatory drug.
Proceedings of the National Academy of Science, April 19 (2016)
 
Disulfiram to activate dormant-HIV
By FABIOLA SCHORER-CORTINAS
Advances in HIV research have provided us with powerful antiretroviral drugs to eradicate HIV from the blood. However the virus can still be in a dormant state elsewhere and re-emerge should the patient stop taking the drugs. Julian Elliot et al. conducted a clinical trial with the well-known anti-alcohol drug disulfiram and observed how this drug also flushes out dormant HIV in infected people. Disulfiram may be suited for future studies in combination with a second drug to activate latent HIV and then eliminate it over a finite period.
The Lancet HIV, November 17 (2015)
 
Relevance of gut microbiota for cancer immunotherapy
By FABIOLA SCHORER-CORTINAS
The presence of certain gut microbes might be responsible for a more effective cancer immunotherapy. Vetizou et al. have explored the role of the gut microbiota by implanting melanoma tumors on mice with different commensal bacteria. The researchers found that tumors grew less aggressively and even responded better to an anti-PD-L1 immunotherapy on some mice than others. The difference was linked to the presence of certain Bifidobacterium species in the GI tract of mice responding positively against cancer tumors. To prove the latter, a cocktail of Bifidobacterium species was then added to the other mice and indeed, the anti-tumor response was stronger. These interesting results might not be directly extrapolated to humans, but might help us understand why different cancer immunotherapies vary among patients.
Science, November 5 (2015)
 
Targeting HIV-infected cells by DARTs
By FABIOLA SCHORER-CORTINAS
The strategy to eliminating HIV consists of a “kick and kill” tactic by activating latent HIV expression and then immune-mediated elimination. Focusing on the latter, Sloan et al. designed Dual-Affinity Re-Targeting (DART) molecules that target both killer T cells and HIV-infected cells containing viral envelope protein (Env). These engineered molecules induce killing of the HIV-infected cells and reduce the levels of HIV expression in blood cells from HIV patients on antiretroviral therapy, pointing towards efficient DART-mediated killing of HIV reservoir cells. Next steps to prove the DART efficacy will need to be performed in vivo; however, this study shows the potential of these molecules for HIV therapy.
PLOS Pathogens,Nov 5 (2015)
 
Universal flu vaccination
By FABIOLA SCHORER-CORTINAS
Seasonal flu vaccines are usually based on a prediction of the strains likely to dominate that year. Therefore, protection is limited to a match between the strains in the vaccine and the circulating virus. By adding an adjuvant to stimulate both innate and adaptive immunity, Brendon Chua and colleagues have improved the effectiveness of an influenza A vaccine in mice. The TLR2 agonist-based lipopeptide adjuvant, R4Pam2Cys, is a synthetic lipopeptide that mimics a component of the bacterial membrane and is therefore capable of triggering antigen-independent immunity. This adjuvant-boosted vaccine would therefore cross-protect against different strains and could also protect against flu strains from other species.
mBio, October 27(2015)
 
Nanocarrier to carry new hope to battle brain cancer
By FABIOLA SCHORER-CORTINAS
Gliobastoma multiforme (GBM), a type of brain cancer, is known for being inoperable and resistant to therapies. One of the main problems for its successful therapy relies on the prevention of local accessibility of therapeutic drugs by the blood brain barrier. Recently, Ting Xu et al. developed a special nanocarrier formed from amphiphilic peptides and polymers, called 3HM. The novel nanocarriers have been found to successfully cross the blood brain barrier and accumulate inside GBM tumors in rats. This finding will open the possibility of treating GBM via intravenous drug administration rather than common invasive methods.
Journal of Controlled Release,Sept 27 (2015)
 
Glutamine analogue reverses cerebral malaria
By FABIOLA SCHORER-CORTINAS
Cerebral malaria is a fatal complication of infection with Plasmodium falciparum and there are currently no treatments available. Gordon et al. have recently reported the potential of targeting glutamine metabolism to arrest the disease. The authors infected mice with Plasmodium berghei ANKA to induce experimental cerebral malaria and then treated them with a glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON), which blocks glutamine transport and inhibits glutaminase. Indeed, DON treatment prevented the development of neurological signs of disease: it restored the blood-brain barrier integrity and reduced cerebral swelling. This study identifies DON as a promising candidate for treating cerebral malaria.
Proceedings of the National Academy of Sciences,August 26 (2015)
 
Syndecan-4 as a novel target for allergic inflammation
By FABIOLA SCHORER-CORTINAS
Polte and colleagues found that Syndecan-4 has a critical role in triggering asthma. Syndecan-4, a transmembrane heparin sulfate proteoglycan, is expressed on antigen presenting cells and plays a crucial role in allowing their migration to lymph nodes to initiate an immune response. Using Syndecan-4 deficient mice or an anti-Syndecan-4 antibody the researchers showed that blocking this molecule reduced asthma phenotypes. These findings indicate that this molecule might be a novel target for therapeutic intervention in allergic inflammatory diseases.
Nature Communications,July 13 (2015)
 
Modified T cells to fight cancer
By FABIOLA SCHORER-CORTINAS
Obenaus et al. created transgenic mice that are able to produce human T cell receptors directed against specific tumor cells. Specifically, the researchers isolated human T cell receptors that recognize a target antigen called MAGE-A1. This antigen is expressed on the surface of malignant tumor cells of some cancer types like multiple myeloma; but not on healthy cells. After some successful trials on mice and human cells in vitro, the scientists are now planning an initial clinical trial by adding the T cell with the modified T cell receptors targeting MAGE-A1 into multiple myeloma patients. Approval for this clinical trial may pave the way towards more effective immunotherapies against cancer.
Nature Biotechnology, March 16 (2015)
 
Nanovectors as “swiss-army-knifes” in cancer treatment
By CHRISTOPH SCHNEIDER
Mathew Hembury et al. developed a nanoparticle, which combines therapeutic and diagnostic functionalities. The gold-silica nanoparticles are highly biocompatible, emerge photonic and magnetic properties, which are beneficial for imaging-based diagnostics and that combine chemotherapy with photothermal therapy. Tested in a mouse model of colorectal cancer, the nanoparticles not only allowed a precise surveillance of the cancer but also decreased the tumor burden significantly.
Proceedings of the National Academy of Science, Feb 4 (2015)
  
New biomarkers for HIV
By CHRISTOPH SCHNEIDER
If patients with advanced HIV suffer from a co-infection with tuberculosis, the antiretroviral therapy during antibiotic treatment of tuberculosis is risky and can lead to to tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) or even death soon after the initiation of therapy. Shruti Ramivohan et al. performed a cohort study in Botswana with over 200 patients. They identified several biomarkers markers, including GM-CSF and Eotaxin, which substantially differ between patients encountering early mortality or tuberculosis-associated IRIS. The newly discovered biomarkers could help distinguishing the two groups before the start of antiretroviral treatment and would provide valuable indications for the subsequent treatment strategies.
The Lancet Infectious Disease, Feb 9 (2015)
 
 Treating diabetes by boosting T cells in the fat tissue
By CHRISTOPH SCHNEIDER
FoxP3+ regulatory T (Treg) cells play important roles in tissue homeostasis. The lack of Treg cells is associated with severe autoimmune diseases. Treg cells within adipose tissue prevent obesity-associated inflammation, latter of which can lead to diabetes type 2. A recent study by Ajithkumar Vasanthakuma et al. associates the homeostatic function of Treg cells within adipose tissue not only with the prevention of inflammatory reactions but also with sustained insulin sensitivity. Interestingly, IL-33 was found to boost the Treg cell population within the adipose tissue, thereby efficiently preventing the development of diabetes type 2.
Nature Immunology,  Jan 19 (2015)
 
IgG antibodies against microbial attachment sites
By CHRISTOPH SCHNEIDER
While the anti-protein binding properties of IgG antibodies have been extensively investigated in the last decades, little is known about the anti-carbohydrate binding properties of IgG. Christoph Schneider et al. investigated the potential of IVIG (pooled IgG) to bind to carbohydrates on a glycan array involving 610 immobilized glycans. A surprisingly universal carbohydrate-binding repertoire and a structure-relationship in terms of immunogenicity was found, which might be exploited for the design of glycovaccines. Furthermore, the study revealed the potential of IgG to interact with host attachment sites of viruses, bacteria and bacterial toxins. Such specific anti-attachment site antibodies might be used in the context of so-called anti-adhesion therapy.
Science Translational Medicine,  Jan 7 (2015)
 
Mimicking antibodies
By CHRISTOPH SCHNEIDER
Monoclonal antibodies and other peptide-based therapeutics are of great importance for the treatment of many diseases. However, the high molecular weight and the peptide structure relate the use of many peptide based therapeutics to several limitations such as allergic reactions, poor tissue penetration or a lack of oral bioavailability. Patrick J McEnaney et al. now report the development of novel synthetic molecules with the targeting and effector-cell-activating functions of an antibody, while being less than 5% of its molecular weight. These so-called SyAMs (synthetic antibody mimics) easily penetrate tissue, are selective, bind only to activating Fc receptors and avoid the deposition of complement in the tissue. SyAMs display a promising tool in fighting a variety of cell- or virus-based diseases.
Journal of the American Chemical Society, Dec 16 (2014)
 
3D-Vaccine platform modulate immune cells and increase vaccine efficacy
By CHRISTOPH SCHNEIDER
In order to increase the efficacy of vaccines, Jaeyun Kim et al. have developed a silica-based vaccine platform, which spontaneously assembles to a scaffold, as soon as it has been administered. By the establishment of an infection-mimicking microenvironment, this biodegradable 3D scaffold has the potential to efficiently recruit and manipulate immune cells and might serve as a multifunctional vaccine modulating immune cells and provoking immune responses. As the platform can be loaded with a variety of antigens and drugs, the potential field of clinical application is enormous.
Nature Biotechnology, Dec 8 (2014)
 
 Reversing Type 2 diabetes
By FABIOLA SCHORER-CORTINAS
Type 2 diabetes has risen steeply in the last decade, possibly as a cause of excess weight and a sedentary way of living.  Suh et al have recently reported an injection of the protein FGF1 that in mice not only keeps sugar levels under control, but reverses insulin insensitivity. The mechanism of FGF1 is not fully elucidated yet but seems as a promising tool for glucose control. Human trials of FGF1 are planned in order to use this target as a therapeutic drug.
Nature, July 16 (2014)
 
New drug targets for memory impairment in Alzheimer’s disease
By FABIOLA SCHORER-CORTINAS
There is currently no cure for Alzheimer’s disease, which is the most common cause of dementia. Seonmi Jo et al have reported that reactive astrocytes, frequently observed in Alzheimer’s patients, produce abnormally and in high quantities the neurotransmitter GABA by the enzyme monoamine oxidase B (MAO-B) and release it though the Bestrophin-1 (Best1) channel. The released GABA then inhibits neighboring neurons and cause impairment in synaptic transmission, plasticity, and memory. By blocking MAO-B or Best1 in the brains of Alzheimer’s disease model mice, the authors successfully ameliorate damages in neuronal features. This study is therefore of great clinical relevance, as new therapeutic targets are proposed for treating Alzheimer’s disease.
Nature Medicine, June 29 (2014)
 
Linear ubiquitination regulates directly immunity
By FABIOLA SCHORER-CORTINAS
A new substrate of the linear ubiquitin assembly complex (LUBAC), consisting of HOIL-1, HOIP, and Sharpin has been implicated in reducing inflammation in human autoimmune and hyper-inflammatory diseases, such as rheumatoid arthritis and Type 2 diabetes. Rodgers et al have recently showed that HOIL-1L , plays an essential role in the formation of the NLRP3-ASC inflammasome signaling complex. It was found in vivo, that mice lacking HOIL-1L are completely resistant to sepsis. With these findings, the authors provide a new therapeutic strategy for reducing inflammation in disease.
The Journal of Experimental Medicine, June 23 (2014)
 
 Including fiber in daily consumption helps protect from asthma
By FABIOLA SCHORER-CORTINAS
A recent study from Trompette et al has shown that dietary fermentable fiber content modified the intestinal microbiota. As fermentable fibers reach the intestine, they promote the outgrowth of bacteria from the Bacteroidetes phylum, which consequently ferment the fibers and transform them into short-chain fatty acids. These fatty acids then enter the bloodstream and influence the development and functionality of immune cells, which eventually trigger a weaker allergic airway inflammation. These results are clinically relevant as they support the fact that targeting diet is a crucial strategy not only for intestinal diseases but also for respiratory inflammatory diseases.
Nature Medicine, Jan 5 (2014)
  
Inhibition of antioxidants for blocking cancer cells
By FABIOLA SCHORER-CORTINAS
Non-small-cell lung cancers (NSCLC) is the most common type of lung cancers and are often related with poor prognosis. Adenocarcinoma is a subtype of NSCLC and is characterized by overproducing an antioxidant protein called superoxide dismutase 1 (SOD1) as a mean to escape immunologic response via reactive oxygen species. Recently, Glasauer et al reported a SOD1 pharmacological inhibitor, called ATN-224, that arrested the growth of human NSCLC cells and induced their death. Therefore, this antioxidant inhibition by ATN-224 has potential clinical applications for the treatment of patients with NSCLC.
Journal of Clinical Investigation, Jan 2 (2014)
  
Jumping genes linked to schizophrenia
By FABIOLA SCHORER-CORTINAS
Bundo et al reported that brains of people with schizophrenia present higher numbers of retrotransposons, or jumping genes, in comparison to healthy controls. Specifically, it was found that a retrotransposon called long interspersed nuclear element-1 was present in the brains of schizophrenia patients and in animal models of schizophrenia. Finding a specific role of what these jumping genes do in the brain is an area of current interest in research.
Neuron, Jan 2 (2014)
 
 
PKM2: Vital protein for cancer development
By FABIOLA SCHORER-CORTINAS
Jiang et al have reported that the tumor-specific pyruvate kinase M2 (PKM2) is a central player in the orderly cell division that allows cancer cells to proliferate. These findings are of significant importance for the development of new therapeutic strategies having PKM2 a pivotal role in controlling cell-cycle progression and tumorigenesis.
Molecular Cell, Dec 5 (2013)
  
Promising personalized vaccine for Gliobastoma multiforme tumors
By FABIOLA SCHORER-CORTINAS
Glioblastoma multiforme (GBM) tumors, are aggressive tumors invading the brain and are often resistant to standard therapies. Bloch et al recently described how patients with GBM treated with a heat-shocked protein peptide complex (HSPPC)-96 vaccination showed improved survival compared to those treated with usual therapies. The HSPPC-96 vaccine is produced individually for each patient using that patient’s own resected tumor tissue, in an effort to activate the immune system response against remaining brain tumor cells. The HSPPC-96 vaccine is currently in phase II trial and might offer a valuable immunotherapy to extend the lives of people suffering GBM.
Neuro-Oncology, Dec 12 (2013)
 
 Next-generation antimalarial drug
By FABIOLA SCHORER-CORTINAS
In a continuous effort to eradicate malaria, different research groups have focused on targeting Plasmodium essential pathways for all life stages. McNamara et al have identified a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class involved in blocking the intracellular development of this parasite. By interacting with the ATP-binding pocket of PI(4)K, the imidazopyrazines showed a great potential for the prevention, treatment and elimination of malaria.
Nature, Dec 12 (2013)