Development Of Cytokine Storm Research Articles

Nanomedicine therapies modulating Macrophage Dysfunction: a potential strategy to attenuate Cytokine Storms in severe infections.

Cytokine storms, defined by the dysregulated and excessive production of multiple pro-inflammatory cytokines, are closely associated with the pathology and mortality of several infectious diseases, including coronavirus disease 2019 (COVID-19). Effective therapies are urgently needed to block the development of cytokine storms to improve patient outcomes, but approaches that target individual cytokines may have limited effect due to the number of cytokines involved in this process. Dysfunctional macrophages appear to play an essential role in cytokine storm development, and therapeutic interventions that target these cells may be a more feasible approach than targeting specific cytokines. Nanomedicine-based therapeutics that target macrophages have recently been shown to reduce cytokine production in animal models of diseases that are associated with excessive proinflammatory responses. In this mini-review, we summarize important studies and discuss how macrophage-targeted nanomedicines can be employed to attenuate cytokine storms and their associated pathological effects to improve outcomes in patients with severe infections or other conditions associated with excessive pro-inflammatory responses. We also discuss engineering approaches that can improve nanocarriers targeting efficiency to macrophages, and key issues should be considered before initiating such studies.

32: Peripheral Infusion of Human Umbilical Cord Mesenchymal Stem Cells Improves Acute Liver Failure in Monkeys: A Preclinical Study

Introduction: Acute liver failure (ALF) is associated with high mortality, and liver transplantation is the only treatment option. We have previously reported the pathophysiological mechanisms of ALF in a non-human primate model challenged by α-amatoxin. Our data highlighted the critical role of circulating monocyte-derived IL-6 in the initiation and acceleration of cytokine storm and ALF. We also reported that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) disrupts the development of cytokine storm by inhibiting the activation of circulating monocytes, offering a promising therapeutic strategy to this lethal syndrome. However, it is unknown whether this treatment is still effective when the cytokine storm is fully developed. This study was designed to evaluate the efficacy of hUC-MSC treatment in rhesus monkeys with fully developed ALF. Methods: Sixty healthy male rhesus monkeys, aged at 4–6 years, were randomly and averagely divided into two groups and the monkeys in each group were intraperitoneally administered α-amatoxin at either 20 or 40 μg/kg, respectively. Forty-eight hours after toxin injection, monkeys in each group were further averagely divided into 3 groups and were treated either 1x107 hUC-MSCs, 2x107 hUC-MSCs, or equal value of saline. Blood and liver specimens were harvested and imaging examination was performed at indicated time points. Results: 48 hours after toxin exposure, the liver indices of the monkeys increased significantly. All the monkeys received 20 μg/kg toxin survived and their sera indices returned to normal levels at 312 h, 84 h or 60 h following infusion of saline or 1U cells or 2U cells, respectively. However, in animals received 40 μg/kg toxin, 1, 2, or 3 animals survived when they were treated with saline, 1U cells or 2U cells, respectively. Despite the high mortality, hUC-MSC therapy has also shown potential to protect liver histology and improve system aberrance. Discussion and conclusion: Although systemic inflammatory response has been thoroughly activated, delayed hUC-MSC treatment can decrease cytokine storm and improve liver tissue and systemic inflammatory reaction in a dose-dependent manner. This study provides a promising strategy for the treatment of ALF.

Adiposity As a Principal Component of Lethal Cytokine Storm Following Cancer Immunotherapy in Aged Mice

The use of immunotherapy (IT) in cancer has recently resulted in impressive responses. Yet, their usages, especially those involving cytokine therapies, have also resulted in the induction of severe systemic toxicities often not previously characterized in their preclinical animal studies. Our laboratory has demonstrated that treatment of EL4 lymphoma with a combination immunotherapy consisting of monoclonal agonistic antibody CD40 and IL-2 resulted in significant anti-tumor responses leading to overall increases in survival using young inbred mice (2-6 months of age). Yet, the majority of hematological cancers occur in aged individuals, with most diagnoses occurring past the age of 60. We now demonstrate that systemic immunotherapy administration in aged (>16 months of age), but not young, mice resulted in the induction of a rapid cytokine release syndrome, also known as “cytokine storm”, culminating in multi-organ damage (liver, lung, and gut) leading to rapid lethality by day 2 of treatment. Aging is accompanied by an overall redistribution of body mass, with a decrease in lean muscle mass and increase in adiposity. Similarly, we found that normal aging in inbred mice housed under specific pathogen free conditions was accompanied by increases in visceral fat that was similar to young obese (ob/ob or diet-induced obese [DIO]) mice. We therefore assessed the impact of aging and obesity on inflammatory responses to cancer immunotherapeutics. We determined the effects of increased body fat on systemic immunotherapy tolerance in aged mice compared to young obese mice. Both young ob/ob and DIO generated pro-inflammatory cytokine (ie TNFa and IL6) levels and organ pathologies comparable to aged WT mice following immunotherapy, culminating in rapid lethality after several days of therapy. We observed that young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNFa+ macrophages in comparison to young lean mice with immunotherapy. Administration of aCD40/IL-2 with macrophage depletion or TNF-blockade prevented the development of cytokine storms within young obese mice, providing protection from lethality, suggesting that the toxicity was macrophage mediated through increases in TNFa. Calorie-restricted aged mice contain less visceral fat and upon aCD40/IL-2 administration displayed reduced cytokine levels, protection from organ pathology, and protection from lethality. Our data demonstrates adiposity as a critical factor in the age-associated inflammatory pathologic responses to systemic anti-cancer immunotherapy and may have a significant impact when immunotherapy is used clinically within cancer therapy regimens. These data also underscore the critical importance of taking aging and body fat into consideration with preclinical assessments. DisclosuresNo relevant conflicts of interest to declare.