New approach prevents GVHD, unintended consequences

Scientists at the University of Freiburg have shown that antibody-based prophylactic treatment after bone marrow transplant (BMT) could prevent infections without reducing the diversity of the gut microbiome. BMT is a cure for a number of blood cancers, but it has a very high complication and death rate itself. A frequent and serious complication of bone marrow transplants is acute graft-vs.-host disease (aGVHD), where the transplanted marrow mounts an immune response against the transplantee. Infections can set off aGVHD, and prophylactic antibiotics can reduce the chance of aGVHD in the short term. But antibiotics reduce the diversity of the gut microbiome, and such reduced diversity also increases the risk of aGVHD. In their experiments, the team tested the use of vaccination or antibodies to the conserved microbial surface polysaccharide poly-N-acetyl glucosamine (PNAG), which is expressed on more than 30 different pathogens. They showed that in animal studies, anti-PNAG treatment reduced aGVHD-related mortality. Because both antibodies and vaccinations would affect only pathogens that are outside of their natural gut habitat, those treatments did not reduce gut microbiome diversity. "In summary, we demonstrate that the novel properties of anti-PNAG antibody treatment and vaccination against PNAG reduced GVHD-related mortality," the authors wrote. "This could be translated into a clinical application, given the modest toxicity profile of vaccination and the availability of fully human anti-PNAG antibodies, both of which have been tested in phase I trials in humans." Their results appeared in the Sept. 16, 2019, online issue of the Proceedings of the National Academy of Sciences.

Thai vaccine works better in South Africa

Investigators at the University of the Witwatersrand have shown that the vaccine regimen used in the RV-144 "Thai" trial, the first trial to demonstrate any protective efficacy for an HIV vaccine, elicited a stronger immune response in a South African cohort than it had in the original Thai cohort. HIV has evolved into different subtypes, or clades, and the predominant clade in Thailand is different from that in South Africa. However, the team tested the RV-144 regimen in South Africa as part of a broader vaccine development plan. Unexpectedly, a detailed analysis of T-cell and antibody responses in the South African cohort showed that their immune responses were often stronger than those of the original vaccines, though like in the RV-144 trial, responses were not durable. "Our data suggest that the breadth of immune responses elicited by this vaccine regimen may allow for vaccine protection that could extend beyond the clade used for immunogen development, and potentially function as a more global vaccine." The trial results were published in the Sept. 18, 2019, issue of Science Translational Medicine.

Senescent cells eat their neighbors

P53 is a tumor suppressor, but in breast cancer patients, it also leads to chemotherapy resistance, as p53 wild-type cells frequently go into senescence, rather than apoptosis, when treated with chemotherapy. Researchers from Tulane University have now shown that such senescent cells undergo gene expression changes that allow them to take on macrophage-like eating capabilities, which leads them to engulf neighboring cells, the authors wrote, "at a remarkable frequency...suggesting an abundant source of energy and building blocks for these cells that then drive relapse and poor survival." The authors concluded that their findings "suggest compelling explanations for how senescent cells persist in dormancy, how they manage the metabolically expensive process of cytokine production that drives relapse in those tumors that respond the worst, and a function for their expanded lysosomal compartment." Their work was published in the Sept. 17, 2019, early online edition of the Journal of Cell Biology.

Indirect targeting can affect serine production

Investigators at the Massachusetts Institute of Technology have identified levels of the enzymatic cofactor NAD+ as a limiting factor for cells' ability to synthesize serine. Cells can make nucleotides from serine, and serine synthesis is up-regulated in many tumor cells, despite the fact that they also take up serine from the extracellular environment. In their work, the researchers showed that in cells that increased their serine synthesis, levels of NAD+ constrained how much serine they were able to make. "NAD+-depleting drugs could... enhance response to dietary serine limitation," the authors wrote. Additionally, "a better understanding of how differential pathway use by cancer cells creates metabolic liabilities could suggest additional opportunities to target metabolism for therapeutic benefit." They reported their findings in the Sept. 16, 2019, online issue of Nature Metabolism.

Sympathetic nervous system can protect from autoimmunity

Stress may be bad for your health, but the stress neurotransmitter norepinephrine was protective from autoimmunity in autoimmune encephalitis (EAE), the closest mouse model of multiple sclerosis. The nervous and immune system are intimately connected, and the sympathetic nervous system modulates immunity, but its involvement in autoimmunity has been unclear. In their experiments, the team showed that in mice with EAE, sympathetic nervous system (SNS) signaling via the beta-2 adrenergic receptor (Adrb2) reduced the generation of pathogenic T cells by suppressing the production of pro-inflammatory cytokines. "Collectively, these results uncover a suppressive role for the SNS in CNS autoimmunity while they identify potential targets for therapeutic intervention," the authors wrote. They reported their results in the Sept. 17, 2019, issue of Cell Reports.

Targeting genes while avoiding their homologs can fix CGD

Chronic granulomatous disease (CGD) is an immunodeficiency disease that results from mutations in the enzyme NADPH oxidase. Those mutations prevent macrophages from functioning properly, and result in susceptibility to severe bacterial and fungal infections. Though treatment options have improved and CGD is no longer uniformly fatal during childhood, bone marrow transplant remains the only curative option, and less dangerous treatments are urgently needed. There is one mutation found in the vast majority of CGD cases, making gene therapy an attractive option. However, there are two pseudogenes with high homology to NADPH oxidase in the human genome, necessitating the development of an editing system that will avoid those pseudogenes, as simultaneously inducing breaks in the target gene and the pseudogenes could lead to large-scale deletions or inversions during repair attempts. Researchers at Hannover Medical School have developed an approach in induced pluripotent stem cells that could specifically target the gene. "Functional assays revealed restored NADPH oxidase activity and killing of bacteria in corrected phagocytes as well as the specificity of this approach," they wrote. Their work appeared in the Sept. 19, 2019, issue of Stem Cell Reports.

Lymphocytes check brain's privilege

Scientists at the Technical University of Munich and the German Cancer Research Center have shown that lymphocytes are retained in the brain through signaling of the chemokine CCL19, and that astrocyte-produced CCL19 increased during aging, increasing the number of lymphocytes in the brain and, thus, the risk of CNS lymphoma (CNSL). Using in vivo imaging, the investigators demonstrated that although the brain is an immunoprivileged site, adaptive immune cells regularly entered the brain. They usually left quickly, guided by signaling of CXCL12. However, CCL19 counteracted CXCL12's effects, leading to an increased risk of CNS lymphoma formation. "We have developed a non-surgical model of CNSL with an intact [blood-brain barrier] in immunocompetent mice, which may be used to investigate mechanisms of lymphoma cell entry in the brain at the earliest stages of CNSL" or test prevention strategies, the authors wrote. Moreover, their results "might be exploited prophylactically to prevent LC dissemination to the CNS." They reported their findings in the Sept. 16, 2019, issue of Cancer Cell.

A cure for the common cold, and paralysis

Enteroviruses are a large group of viruses, and the diseases they cause range in severity from polio to the common cold. Researchers at the University of California at San Francisco and Stanford University have found that the enzyme SETD3 was "critically important for viral infection by a broad panel of EVs," – enteroviruses – "including rhinoviruses and non-polio EVs increasingly linked to severe neurological disease such as acute flaccid myelitis (EV-D68) and viral encephalitis (EV-A71)." SETD3 is a methyltransferase, but its role in EV infection was independent of its methylation activity. Instead, SETD3 interacted with the viral protein 2A in a way that was critical for viral RNA replication. "Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections," the authors wrote. They reported their results in the Sept. 16, 2019, issue of Nature Microbiology.

Senolytics work as advertised

Researchers at Mayo Clinic have demonstrated that senolytic drugs reduced the load of senescent cells in an open-label clinical trial of adults with diabetic kidney disease. Senescent cells, which have stopped dividing but are not in the process of active apoptosis, secrete a number of toxic factors and are being recognized as important contributors to age-related diseases. There are approved drugs that can push senescent cells into apoptosis, and early stage clinical work has shown that treatment with such senolytics can improve outcomes in patients. But a direct demonstration that they decrease senescent cell burden has been lacking. The Mayo team treated nine patients with a combination of cancer drug Sprycel (dasatinib, Bristol-Myers Squibb Co.) and dietary supplement quercetin (D+Q), and showed that the number of senescent cells in adipose tissue decreased after three days of treatment, as did adipose-associated macrophages. The team concluded that "'hit-and-run' treatment with senolytic agents, which in the case of D+Q have elimination half-lives of [less than] 11 [hours], is sufficient to decrease senescent cell burden in humans. Thereafter, senescent cell burden remains low for days to weeks." They reported their results in the Sept. 18, 2019, issue of eBiomedicine.

 

No Comments