Cell-based approaches for the treatment of systemic inflammation

Abstract

Acute and chronic solid organ failures are costly disease processes with high mortality rates. Inflammation plays a central role in both acute and chronic organ failure, including heart, lung and kidney. In this regard, new therapies for these disorders have focused on inhibiting the mediators of inflammation, including cytokines and free radicals, with little or no success in clinical studies. Recent novel treatment strategies have been directed to cell-based rather than mediator-based approaches, designed to immunomodulate the deleterious effects of inflammation on organ function. One approach, cell therapy, replaces cells that were damaged in the acute or chronic disease process with stem/progenitor technology, to rebalance excessive inflammatory states. As an example of this approach, the use of an immunomodulatory role of renal epithelial progenitor cells to treat acute renal failure (ARF) and multiorgan failure arising from acute kidney injury is reviewed. A second therapeutic pathway, cell processing, does not incorporate stem/progenitor cells in the device, but rather biomimetic materials that remove and modulate the primary cellular components, which promote the worsening organ tissue injury associated with inflammation. The use of an immunomodulating leukocyte selective cytopheretic inhibitory device is also reviewed as an example of this cell processing approach. Both of these unconventional strategies have shown early clinical efficacy in pilot clinical trials and may transform the therapeutic approach to organ failure disorders.

Fig. 1.

Survival of citrate vs. heparin in SCD in the control subset of the RAD trial.

Fig. 2.

Microscopy of the sham cartridges after patient treatment demonstrated adherent leukocytes on the outer surface of the membranes of the cartridge along the blood flow path within the extracorporeal circuit.

Fig. 3.

SCD-C circuit (A) depicting locations of regional citrate anticoagulation administration and calcium infusion. Porcine sepsis model treated with SCD-C and SCD-H show differences in absolute NE counts over the duration of therapy (B), cardiac output (C) and NE infiltration in lung: SCD-H (D), SCD-C (E).