Astrocyte-T cell crosstalk regulates region-specific neuroinflammation

During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions. While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood. Here, we demonstrate that astrocytes exhibit region-specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation. Analysis of cytokine receptor expression in human astrocytes showed region-specific responsiveness to Th1 and Th17 inflammatory cytokines. Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM-1 and CXCR7 that is both cytokine and CNS region-specific. Using in vivo models of spinal cord versus brain stem trafficking of myelin-specific T cells and astrocyte-specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM-1 and CXCR7 in these locations. Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region- and cytokine-specific modulation of localizing cue expression by astrocytes. These findings identify a role for inflammatory cytokines in mediating local astrocyte-dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation.     

CRISPR-Cas9-Edited Tacrolimus-Resistant Antiviral T Cells for Advanced Adoptive Immunotherapy in Transplant Recipients

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Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy.

This report presents the light microscopic morphology found at autopsy in 59 patients who participated in an organized controlled trial of extracorporeal oxygenation as therapy for acute respiratory failure. Observations were recorded as objectively as possible and were analyzed by computer. The experimental therapy produced no specific alteration in the observed pulmonary lesions. Many of the lesions tabulated had significant correlation coefficients with time, all of which were higher when correlated with the duration of respiratory failure than with the duration of the entire acute illness. The rapid progression of the lesions to fibrosis is emphasized as is the predilection of both early and late lesions to involve alveolar ducts to a far greater degree than the distal alveolar spaces. A unifying mechanistic hypothesis consistent with these observations, as well as others, is that the lesions may result as much from oxygen damage as from the original acute illness.     

Refining indications for contemporary surgical treatment of renal cell carcinoma metastatic to the pancreas

Background:

The pancreas is a rare location for metastatic disease, with only 2–11% of all pancreatic tumours being of non-primary origin. It is also uncommon for renal cell carcinoma (RCC) to metastasize to the pancreas (1–3% of cases) and, when it does, it typically occurs substantially after index nephrectomy. It is not known whether all pancreatic metastases need be resected because today''s chemo- and biological therapies are increasingly effective in controlling advanced disease.

Methods:

Six patients with a variety of symptoms are discussed. Four patients presented with recurrent gastrointestinal bleeding, ranging from occult to life-threatening in severity.

Results:

The four patients with gastrointestinal bleeding had RCC metastases that had eroded into the duodenum and were successfully controlled by palliative pancreaticoduodenectomy or completion pancreatectomy. The other two patients were treated using different chemotherapeutic or biological agents.

Conclusions:

Renal cell carcinoma metastases to the pancreas typically occur long after index nephrectomy. Although clinical presentation is variable, palliative resection should be reserved for those who develop complications, such as upper gastrointestinal bleeding, and, in other series, obstructive jaundice. Routine debulking resections do not appear to be indicated because current biological therapies effectively and reliably control disease over long periods.     

Malignancy may adversely influence the quality and behaviour of oocytes

A case series of eight cycles of in-vitro fertilization (IVF) in five women diagnosed with malignant disorders is presented. These patients chose to defer definitive treatment for a chance for preservation of potential fertility. The response of these patients to ovarian stimulation, and the outcome, was compared with 17 IVF cycles in 12 age- matched patients with isolated tubal infertility. An apparent adverse influence of malignant disease on the quality and behaviour of oocytes was observed. Despite a comparable total number of oocytes per cycle in the two groups, a significantly reduced percentage of mature oocytes was retrieved per cycle from patients with malignant diseases. The oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared to the controls. We propose that neoplastic processes, irrespective of the site or cell of origin, may have a detrimental impact on the biology of oocytes, an effect akin to that seen on spermatozoa in men with certain malignancies.      

Oestradiol‐Induced Synapse Formation in the Female Hippocampus: Roles of Oestrogen Receptor Subtypes

During the oestrus cycle, varying spine synapse density correlates positively with varying local synthesis of oestradiol in the hippocampus. In this context, the roles of the oestrogen receptor (ER) subtypes ERα and β are not fully understood. In the present study, we used neonatal hippocampal slice cultures from female rats because these cultures synthesise oestradiol and express both receptor subtypes, and inhibition of oestradiol synthesis in these cultures results in spine synapse loss. Using electron microscopy, we tested the effects on spine synapse density in response to agonists of both ERα and ERβ. Application of agonists to the cultures had no effect. After inhibition of oestradiol synthesis, however, agonists of ERα induced spine synapse formation, whereas ERβ agonists led to a reduction in spine synapse density in the CA1 region of these cultures. Consistently, up‐regulation of ERβ in the hippocampus of adult female aromatase‐deficient mice is paralleled by hippocampus‐specific spine synapse loss in this mutant. Finally, we found an increase in spine synapses in the adult female ERβ knockout mouse, but no effect in the adult female ERα knockout mouse. Our data suggest antagonistic roles of ERβ and ERα in spine synapse formation in the female hippocampus, which may contribute to oestrus cyclicity of spine synapse density in the hippocampus.     

Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: Findings in a double‐blind,placebo‐controlled study

Objective

To investigate the effects of intraarticular glucocorticoid treatment on macrophage infiltration, the expression of the chemokines monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1α (MIP‐1α), and the expression of matrix metalloproteinases 1 and 3 (MMPs 1 and 3) and their inhibitors, the tissue inhibitors of metalloproteinases 1 and 2 (TIMPs 1 and 2), in osteoarthritis (OA) synovial membranes.

Methods

Forty patients underwent arthroscopic biopsy before and 1 month after intraarticular injection of glucocorticoids. Twenty‐one patients received 120 mg of methylprednisolone acetate (Depo‐Medrol; Upjohn, Kalamazoo, MI), and 20 patients received placebo (1 patient received placebo in 1 knee and methylprednisolone acetate in the other). Immunoperoxidase staining for the expression of CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 was performed, and the immunostaining was quantified by color video image analysis.

Results

CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining was observed in all synovial membranes. Intraarticular glucocorticoid treatment was associated with a small (30%) but statistically significant (P = 0.048) reduction in CD68+ macrophage staining in the synovial lining layer, but there was no change in the CD68 expression in the synovial sublining layer. No significant differences were observed for MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining in the synovial lining or sublining layers.

Conclusion

Intraarticular glucocorticoids may reduce CD68+ macrophage infiltration into the synovial lining layer, but not the expression of MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 in the synovial membrane, in patients with OA.