Charles A. Dinarello

Bio: Charles A. Dinarello is an academic researcher from University of Colorado Denver. The author has contributed to research in topics: Interleukin & Cytokine. The author has an hindex of 190, co-authored 1058 publications receiving 139668 citations. Previous affiliations of Charles A. Dinarello include University of Guadalajara & Pennsylvania State University.

Targeting of the NLRP3 Inflammasome for early COVID-19

Abstract: Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1 are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1{beta}, triggering both local as well as systemic inflammation. This cascade of inflammatory cytokines in patients with COVID-19 is termed "Cytokine Release Syndrome" (CRS), and is associated with poor outcomes and death. Many studies reveal that blocking IL-1 activities in COVID-19 patients reduces disease severity and deaths. Here we report highly significant circulating levels of IL-1{beta}, IL-1 Receptor antagonist, IL-6, TNF, IL-10 and soluble urokinase plasminogen activator receptor in COVID-19 patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) early in the infection. We observed increased NLRP3 gene expression in myeloid cells correlated with IL-1{beta} gene expression and also with elevated circulating IL-1{beta} levels. We conclude that early in SARS-CoV-2 infection, NLRP3 activation takes place and initiates the CRS. Thus, NLRP3 is a target to reduce the organ damage of inflammatory cytokines of the CRS.

Methods and compositions for treatment of graft rejection and promotion of graft survival

Abstract: Embodiments of the present invention illustrate methods of treating and preventing transplantation and side effects associated with transplantation. In certain embodiments, compositions and methods relate to inhibition of graft rejection and promotion of graft survival. Thus, the invention relates to modulation of cellular activities, including graft rejection, promotion of graft survival, graft versus host rejection, islet cell preservation and conditions commonly associated with graft rejection. Other embodiments relate to the inhibitory compounds comprising naturally occurring and man-made inhibitors of serine protease and inducers of other alpha1-antitrypsin activities.

MABp1 targeting interleukin-1α in hidradenitis suppurativa ineligible for adalimumab treatment: results of the open-label extension period.

Abstract: The emerging situation of patients with moderate-to-severe hidradenitis suppurativa (HS) non-eligible for or not responding to adalimumab generates the unmet need for new therapies. In a previous small-scale randomized clinical trial, MABp1 (also known as bermekimab) showed 60% treatment efficacy compared to 10% of placebo in such patient population. Eight of patients originally randomized to placebo treatment were allowed to participate in an open-label extension (OLE) treatment with MABp1 7.5mg/kg intravenously every other week. HS clinical response (HiSCR) was achieved at the end of the 12-week treatment in six patients (75%). The total number of inflammatory lesions and the international HS4 score were significantly decreased compared to the blinded placebo treatment period. Results support the use of bermekimab as treatment alternative for patients non-eligible or non-responding to adalimumab.

The pathogenesis of atherosclerosis: a perspective for the 1990s

Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

Cancer-related inflammation.

Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Abstract: Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Inflammation in atherosclerosis

Abstract: Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.