Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis.

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.

Evaluation of the immunomodulatory effects of interleukin-10 on peripheral blood immune cells of COVID-19 patients: Implication for COVID-19 therapy.

Objective: Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform. Methods: Two cohorts were evaluated: in "study population A", plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized "COVID-19 patients" and 29 "NO COVID-19 controls" all unvaccinated. In "study population B", 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis. Results: Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in "study population A". Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in "study population B". Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8+ and NK cells. Conclusion: This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.

Negative impact of high body mass index on cetuximab-mediated cellular cytotoxicity against human colon carcinoma cells.

This study assessed the relationship between the ability of Natural Killer (NK) cells to activate antibody-dependent cellular cytotoxicity against human HT29 colorectal cancer cells exposed to cetuximab and the body mass index of the human subjects from whom the NK cells had been obtained. NK cells obtained from 73 human donors were co-incubated with HT-29 human colon cancer cells in the presence or absence of cetuximab. Antibody-dependent cellular cytotoxicity was assessed by measuring LDH release. A significant negative correlation was observed between body mass index and cetuximab-induced antibody-dependent cellular cytotoxicity. NK cells obtained from subjects who were overweight or with obesity were less efficient in killing cetuximab-treated HT29 cells than those derived from normal weight donors. Our results suggest that the success of cetuximab-containing regimens might be impaired in overweight and obese patients with colorectal cancer.

The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies.

SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the "cytokine storm" are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host's cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.

Interactions of single-wall carbon nanotubes with endothelial cells.

Single-wall carbon nanotubes (SWCNTs) could be promising delivery vehicles for cancer therapy. These carriers are generally introduced intravenously, however, little is known of their interactions with endothelial cells, the cells lining vessels and mediating clearance of nanoparticles. Here we show that SWCNTs of 1 to 5 microm in length, both "pristine" and functionalized by oxidation, had limited toxicity for endothelial cells in vitro as determined by growth, migration morphogenesis, and survival assays. Endothelial cells transiently took up SWCNTs, and several lines of data indicated that they were associated with an enhanced acidic vesicle compartment within the endothelial cells. Our findings of SWCNT interactions with endothelial cells suggest these may be optimal vehicles for targeting the vasculature and potential carriers of anti-angiogenic drugs. The implications on their biological activity must be taken into account when considering the use of these nanoparticles for therapeutic delivery of drugs. FROM THE CLINICAL EDITOR: Interactions of single walled carbon nanotubes (SWCNTs) with endothelial cells following IV administration remains unclear. Functionalized and naïve SWCNTs of 1-5 mm in length had limited toxicity to endothelial cells in vitro. Endothelial cells transiently took up SWCNTs and were associated with an enhanced acidic vesicle compartment within the cells. These findings suggest that SWCNTs may be promising vehicles for targeting the vasculature and potential carriers of anti-angiogenic drugs.