Rationale for IL-1 Beta targeted therapy in sickle cell disease for ischemia-reperfusion induced complications

摘要

Sickle cell patients atypically experience exaggerated inflammatory responses to pathogens that normally cause mild respiratory infections in non-sickle cell humans. There appears to be heightened inflammatory responses to pathogens in combination with hypoxia in sickle cell disease. The novelty of this invention provides a new paradigm to explain the exaggerated inflammatory response of sickle cell disease to pathogens especially when accompanied by hypoxic stress. In particular, sickle cell chest injury and other complications associated with ischemia-reperfusion injury caused by vaso-occlusion can involve co-stimulation of the NALP-3 inflammasome by pathogen associated molecular patterns (PAMPs) and hypoxic-induced danger associated molecular patterns (DAMPs), leading to exaggerated pro-inflammatory responses marked by increased IL-1β secretion and subsequent induction of neutrophilic inflammation. This invention thereby provides the immunologic, biologic and biochemical rationale for IL-1β targeted therapies in sickle cell disease to block the pathological effects of IL-1β that leads to exaggerated inflammatory expressions, including neutrophilic inflammation.