2Use of Early Donated COVID-19 Convalescent Plasma Is Optimal to Preserve the Integrity of Lymphatic Endothelial Cells

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune response and the resolution of inflammation from peripheral tissues, including the artery wall. As vascular complications are a key pathogenic mechanism in COVID-19, leading to inflammation and multiple organ failure, we believe that sustaining lymphatic vessel function should be considered to define optimal CPT. We herein sought to determine what specific COVID-19 convalescent plasma (CCP) characteristics should be considered to limit inflammationdriven lymphatic endothelial cells (LEC) dysfunction. CCP donated 16 to 100 days after the last day of symptoms was characterized and incubated on inflammation-elicited adult human dermal LEC (aHDLEC). Plasma analysis revealed that late donation correlates with higher concentration of circulating pro-inflammatory cytokines. Conversely, extracellular vesicles (EVs) derived from LEC are more abundant in early donated plasma (r = -0.413, p = 0.004). Thus, secretion of LEC-EVs by an impaired endothelium could be an alarm signal that instigate the self-defense of peripheral lymphatic vessels against an excessive inflammation. Indeed, in vitro experiments suggest that CCP obtained rapidly following the onset of symptoms does not damage the aHDLEC junctions as much as late-donated plasma. We identified a particular signature of CCP that would counteract the effects of an excessive inflammation on the lymphatic endothelium. Accordingly, an easy and efficient selection of convalescent plasma based on time of donation would be essential to promote the preservation of the lymphatic and immune system of infected patients.