Date Published: April 21, 2016
Publisher: Public Library of Science
Author(s): Svenja Steinfelder, Noëlle Louise O’Regan, Susanne Hartmann, James B. Lok.
Helminths have evolved numerous pathways to prevent their expulsion or elimination from the host to ensure long-term survival. During infection, they target numerous host cells, including macrophages, to induce an alternatively activated phenotype, which aids elimination of infection, tissue repair, and wound healing. Multiple animal-based studies have demonstrated a significant reduction or complete reversal of disease by helminth infection, treatment with helminth products, or helminth-modulated macrophages in models of allergy, autoimmunity, and sepsis. Experimental studies of macrophage and helminth therapies are being translated into clinical benefits for patients undergoing transplantation and those with multiple sclerosis. Thus, helminths or helminth-modulated macrophages present great possibilities as therapeutic applications for inflammatory diseases in humans. Macrophage-based helminth therapies and the underlying mechanisms of their therapeutic or curative effects represent an under-researched area with the potential to open new avenues of treatment. This review explores the application of helminth-modulated macrophages as a new therapy for inflammatory diseases.
Regulation of macrophage activity and function is essential to balance tissue homeostasis, driving or resolving inflammation in most disease processes. The inflammatory or anti-inflammatory activities of macrophages are shaped in a tissue- and signal-specific manner, enabling macrophages to induce various activation patterns and develop specific functional programs (Fig 1) [1,2].
Macrophages are key innate immune cells that encounter helminths upon initial infection. The macrophage immunoregulatory phenotypes that develop during helminth infection divert anti-helminth immunity to induce host tolerance, parasite survival, and repair of any tissue injury caused by larvae or eggs [15,16].
It is important to establish whether, once differentiated, the regulatory phenotype of helminth-modulated macrophages is stable enough to treat chronic diseases. We aim to instigate a discussion by reviewing current data on these macrophages in the treatment of inflammatory diseases (Fig 3).
For macrophage-based therapies, one must consider the possibility of phenotype reversion after transfer. The phenotype and function of a particular macrophage subset develops from the combined integration of tissue-specific and environmental cues, such as inflammation or infection, which can lead to epigenetic imprinting [19,92]; however, the stability of the therapeutic macrophage phenotype must be determined.
The studies discussed herein demonstrate the potential of helminth infections and, in particular, helminth-induced macrophages to treat inflammatory disorders; in some cases, clinical trials are already underway. However, the mode of application must be addressed to determine the safest and most effective route for patients. Is it best to treat the patient with a patent infection or with isolated stages (e.g., eggs)? Is it best to apply specific helminth-derived products (e.g., AvCystatin, ES-62, T. spiralis cathepsin B–like protein) or to stimulate in vitro and reinfuse a patient’s own macrophages? Live infections provide a rapid path to clinical trials compared with identifying and characterising defined products. Nevertheless, live infections remain infectious, and can induce pathological consequences in the host, especially in immunocompromised individuals . In contrast, defined products can be produced recombinantly in high quantities at relatively low costs. Defined products allow efficient site-directed and prolonged application, e.g., through the use of carriers like probiotic bacteria that colonize and release the molecules in targeted tissues . Generating transgenic auxotrophic strains that release powerful helminth products will enable the use of such techniques without risking contamination of the environment. However, helminth products themselves may be immunogenic, and thus, a further therapeutic alternative is the synthesis of small-molecule analogues, as described for ES-62. New targets identified by large-scale technologies (proteomics, metabolomics, genomics) combined with bioinformatics aid the discovery of novel pathways and molecules that can translate helminth–or helminth product–derived immunomodulating strategies into efficient therapies .