Use of Human Preconditioned Phagocytes for Extracorporeal Immune Support: Introduction of a Concept

Abstract

Neutrophils are critical effector cells in humoral and innate immunity and play a vital role in phagocytosis and bacterial killing. If they and/or their specific functions are lacking, then immunoparalysis may occur, and severe diseases like systemic inflammatory response syndrome (SIRS) or sepsis can take a fatal course. In this paper, we discuss the possibility of using preconditioned cells in an extracorporeal biohybrid immune support system. A human promyelocytic cell line was stimulated for different times with all‐trans retinoic acid. The resulting cells displayed major signs and functions of mature neutrophilic granulocytes including oxygen radical production, phagocytosis of living and dead Escherichia coli, Staphylococcus aureus, Candida albicans, intracellular killing, and interleukin production. The cells can be expanded to yield a sufficient cell mass, and subsequent prestimulation results in an expression of specific neutrophil functions. Extracorporeal bioreactor experiments seem to be feasible to test the benefit in immunoparalysis‐associated diseases like SIRS or sepsis.

Extracorporeal cell therapy of septic shock patients with donor granulocytes: a pilot study

“…The efficient removal of live bacteria by granulocytes was both proven in vitro and in the pig-bacteremia model [14,15]. There is already good evidence for removal of bacterial endotoxins as well as interaction on the mediator and cytokine level during this clinical study.…”

“…In in vitro studies [14] and in a large animal model for Gram-positive sepsis [15], we were able to show the proof of principle and promising survival data. Therefore, the bioreactor is now being studied in patients with septic shock in order to show tolerability and feasibility of this kind of complex therapy.…”

Extracorporeal cell therapy with granulocytes in a pig model of Gram-positive sepsis

“…Cell differentiation was induced by 1ϫ10E-5 M all-trans retinoic acid (HoffmannLaRoche, Grenzach-Wyhlen, Germany) for 5 days. After differentiation, the cells showed a phenotype of functional granulocytes with increased production of oxygen radicals, active intracellular killing, and increased phagocytosis with a high reduction rate of Escherichia coli, Staphylococcus aureus, and Candida albicans (28).…”

“…The rationale for such an approach is that on one hand the plasma-modifying capacity of human phagocytes can be used (e.g., to remove antigenic material from the circulation) while on the other hand control over these cells can be maintained (e.g., retention of the cells, their release and breakdown-products; preventing local tissue effects), thereby avoiding potential side effects triggered by GTx. Previous studies revealed that relevant amounts of live and dead bacteria can be removed from human plasma using a phagocytosis cell device (28). Here, we describe the use of such a system in a well-described pig model of multiresistant Gram-positive sepsis (29,30) resembling an onset of sepsis in cases where empirical use of antibiotics fails.…”

Safety Evaluation for a Cell‐based Immune Support System in an Ex Vivo Rat Model of Gram‐negative Sepsis

“…Recently, we demonstrated that a phagocytosis cell device is able to remove living and dead bacteria from plasma at a rate of >70% (in vitro studies) (17). The extracorporeal treatment with the cell device can improve the survival in a pig model of sepsis (18).…”