Functional In Vivo Imaging of Macrophages.

Resident tissue macrophages (RTMs) are specialized phagocytes that are widely distributed throughout the body and are responsible for maintaining homeostasis. Recent advances in experimental techniques have enabled us to gain a greater insight into the actual in vivo biology of RTMs by observing their spatiotemporal dynamics directly in their native environment. Here, we detail a method for live tracking macrophages in a prototypical stromal tissue with high spatial and temporal resolution and great experimental versatility.

Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes.

Clodronate liposomes (Clo-Lip) have been widely used to deplete mononuclear phagocytes (MoPh) to study the function of these cells in vivo. Here, we revisited the effects of Clo-Lip together with genetic models of MoPh deficiency, revealing that Clo-Lip exert their anti-inflammatory effects independent of MoPh. Notably, not only MoPh but also polymorphonuclear neutrophils (PMN) ingested Clo-Lip in vivo, which resulted in their functional arrest.

The Mechanism of Action of Antigen Processing Independent T Cell Epitopes Designed for Immunotherapy of Autoimmune Diseases.

Immunotherapy with antigen-processing independent T cell epitopes (apitopes) targeting autoreactive CD4 T cells has translated to the clinic and been shown to modulate progression of both Graves' disease and multiple sclerosis. The model apitope (Ac1-9[4Y]) renders antigen-specific T cells anergic while repeated administration induces both Tr1 and Foxp3 regulatory cells. Here we address why CD4 T cell epitopes should be designed as apitopes to induce tolerance and define the antigen presenting cells that they target .

Death in the sauna-vitality markers for heat exposure.

In sauna-associated deaths, the vitality of heat exposure is of great importance. Two case reports address this. First, we present the case of a 77-year-old man who was found dead in the sauna of his family home.

Fire exposure after lethal hypothermia.

A 49-year-old woman was found dead in her apartment after a fire began in her building. During the forensic autopsy, 3rd to 4th degree burns were found on the woman's body, but there were no indications that she was alive when the fire started. Interestingly, hemorrhagic gastric mucosa erosions, as well as bloody contents in the esophagus, stomach, and intestines, were observed.

Natural cardiac death after stent implantation with iatrogenic injury of a coronary artery.

In forensic practice, autopsies are regularly carried out in cases of suspected medical malpractice to determine whether a treatment resulted in death. Intraoperative deaths, as well as deaths shortly after an operation, can be particularly suspicious as iatrogenic. We report a case of a 75-year-old woman with a complaint of intermittent angina pectoris who underwent cardiac catheterization.

Chimeric antigen receptor T cells for the treatment of cancer and the future of preclinical models for predicting their toxicities.

Chimeric antigen receptor T-cell therapy has achieved highly promising results in clinical trials, particularly in B-cell malignancies. However, reports of serious adverse events including a number of patient deaths have raised concerns about safety of this treatment. Presently available preclinical models are not designed for predicting toxicities seen in human patients.

Myeloid-derived suppressor cells mediate tolerance induction in autoimmune disease.

In multiple sclerosis (MS) T cells aberrantly recognize self-peptides of the myelin sheath and attack the central nervous system (CNS). Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid-derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity.

Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer's disease-like mice.

Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK).

Extra-thymically induced T regulatory cell subsets: the optimal target for antigen-specific immunotherapy.

Antigen-specific immunotherapy aims to selectively restore tolerance to innocuous antigens in cases of autoimmune or allergic disease, without the need for general immune suppression. Although the principle of antigen-specific immunotherapy was discovered more than a century ago, its clinical application to date is limited, particularly in the control of autoimmunity. This has resulted mainly from a lack of in-depth understanding of the underlying mechanism.

Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.

The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load.

Neuroprotective function for ramified microglia in hippocampal excitotoxicity.

Background: Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.