Functional reprogramming of monocytes in acute and convalescent severe COVID-19 patients

Severe COVID-19 disease is associated with dysregulation of the myeloid compartment during acute infection. Survivors frequently experience long-lasting sequelae but little is known about the eventual persistence of this immune alteration. Herein, we evaluated Toll-like receptor-induced cytokine responses in a cohort of mild to critical patients during acute or convalescent phases (n=97). In the acute phase, we observed impaired cytokine production by monocytes in the most severe patients. This capacity was globally restored in convalescent patients. Yet, we observed increased responsiveness to TLR1/2 ligation in patients that recovered from severe disease, indicating that these cells display distinct functional properties at the different stages of the disease. We identified a specific transcriptomic and epigenomic state in monocytes from acute severe patients that can account for their functional refractoriness. The molecular profile of monocytes from recovering patients was distinct and characterized by increased chromatin accessibility at AP-1 and MAF loci. These results demonstrate that severe COVID-19 infection has a profound impact on the differentiation status and function of circulating monocytes both during the acute and the convalescent phases in a completely distinct manner. This could have important implications for our understanding of short and long-term COVID19-related morbidity.

Immune Modulation in Critically Ill Septic Patients

Sepsis is triggered by infection-induced immune alteration and may be theoretically improved by pharmacological and extracorporeal immune modulating therapies. Pharmacological immune modulation may have long lasting clinical effects, that may even worsen patient-related outcomes. On the other hand, extracorporeal immune modulation allows short-term removal of inflammatory mediators from the bloodstream. Although such therapies have been widely used in clinical practice, the role of immune modulation in critically ill septic patients remains unclear and little evidence supports the role of immune modulation in this clinical context. Accordingly, further research should be carried out by an evidence-based and personalized approach in order to improve the management of critically ill septic patients.

The long-lasting anti-tumor activity of cisplatin affecting the sustainable systemic immune alteration may improve distant-disease free survival of triple-negative breast cancer in patients with a substantial residual tumor following preoperative chemotherapy: A retrospective analysis with translational research.

e12631 Background: Residual disease after preoperative chemotherapy is known to be a poor prognostic factor in triple-negative breast cancer (TNBC). Perioperative use of cisplatin (CDDP) is a well-known, standard treatment for most tumors except breast cancer. In this study, we explore the long-lasting anti-tumor activity of CDDP for TNBC patients. Methods: This research was based on consecutive study of seventy-nine previously untreated stage I–III TNBC patients treated with or without CDDP-based preoperative chemotherapy from 2007 to 2018 at the Kyoto University Hospital. We calculated the residual cancer burden (RCB) using the RCB calculator. All patients were sorted according to their RCB class: the pathological complete response (pCR), and RCB class I (minimal), II (moderate) or III (extensive). Distant disease-free survival (DDFS) was analyzed using the Kaplan-Meier method. Using mass spectrometry, we measured platinum concentrations in serum and normal breast tissue removed during surgery from patients treated with any platinum agents. We examined multiplex cytokine assays from serum sequentially, comparing CDDP and non-CDDP groups. Results: Forty-seven cases were treated with CDDP, and thirty-two did not have CDDP. The pCR rate was 53.2% for the CDDP group and 21.9% without CDDP. Patients with pCR and RCB class I were all distant disease-free. There was no significant difference between each RCB class using CDDP. However, patients belonging to RCB classes II and III with CDDP showed a better prognosis than the same RCB classes without CDDP (hazard ratio = 0.12). Platinum concentrations in serum were correlated with the time from the last dose of platinum agents, but platinum was even detected in serum two years after CDDP. No significant difference was found in the platinum concentrations of serum or normal breast tissue in the pCR and non-pCR groups. We also found that there were significant cytokine expression alteration related to T-cell infiltration only in the CDDP group one year after operation. It is suggested that CDDP may even affect the systemic immune alteration one year after operation. Conclusions: Our data shows that CDDP- based chemotherapy improves DDFS in patients with a substantial residual tumor. CDDP seems to sustain anti-tumor activity for a number of years and interaction with the systemic immune alteration.

Resveratrol in Autism Spectrum Disorders: Behavioral and Molecular Effects

Resveratrol (RSV) is a polyphenolic stillbenoid with significant anti-oxidative and anti-inflammatory properties recently tested in animal models of several neurological diseases. Altered immune alteration and oxidative stress have also been found in patients with autism spectrum disorders (ASD), and these alterations could add to the pathophysiology associated with ASD. We reviewed the current evidence about the effects of RSV administration in animal models and in patients with ASD. RSV administration improves the core-symptoms (social impairment and stereotyped activity) in animal models and it also displays beneficial effects in other behavioral abnormalities such as hyperactivity, anxiety and cognitive function. The molecular mechanisms by which RSV restores or improves behavioral abnormalities in animal models encompass both normalization of central and peripheral immune alteration and oxidative stress markers and new molecular mechanisms such as expression of cortical gamma-amino butyric acid neurons, certain type of miRNAs that regulate spine growth. One randomized, placebo-controlled clinical trial (RCT) suggested that RSV add-on risperidone therapy improves comorbid hyperactivity/non-compliance, whereas no effects where seen in core symptoms of ASD No RCTs about the effect of RSV as monotherapy have been performed and the results from preclinical studies encourage its feasibility. Further clinical trials should also identify those ASD patients with immune alterations and/or with increased oxidative stress markers that would likely benefit from RSV administration.

Helminth infections drive heterogeneity in human type 2 and regulatory cells

Helminth infections induce strong type 2 and regulatory responses, but the degree of heterogeneity of such cells is not well characterized. Using mass cytometry, we profiled these cells in Europeans and Indonesians not exposed to helminths and in Indonesians residing in rural areas infected with soil-transmitted helminths. To assign immune alteration to helminth infection, the profiling was performed before and 1 year after deworming. Very distinct signatures were found in Europeans and Indonesians, showing expanded frequencies of T helper 2 cells, particularly CD161+ cells and ILC2s in helminth-infected Indonesians, which was confirmed functionally through analysis of cytokine-producing cells. Besides ILC2s and CD4+ T cells, CD8+ T cells and γδ T cells in Indonesians produced type 2 cytokines. Regulatory T cells were also expanded in Indonesians, but only those expressing CTLA-4, and some coexpressed CD38, HLA-DR, ICOS, or CD161. CD11c+ B cells were found to be the main IL-10 producers among B cells in Indonesians, a subset that was almost absent in Europeans. A number of the distinct immune profiles were driven by helminths as the profiles reverted after clearance of helminth infections. Moreover, Indonesians with no helminth infections residing in an urban area showed immune profiles that resembled Europeans rather than rural Indonesians, which excludes a major role for ethnicity. Detailed insight into the human type 2 and regulatory networks could provide opportunities to target these cells for more precise interventions.