Release date: 2015-12-24
Choosing the appropriate treatment and dosage based on the molecular markers of a particular disease is the essence of precision medicine, and this is a major research program in the years to come. Studies published in Science by Schukur et al. on the 18th of this month have shown a significant conceptual advance in this area, particularly in the treatment of chronic inflammatory diseases. Studies have shown that synthetic biology can be used to generate and selectively bind to cells that respond to cytokine signaling, providing treatments that are associated with disease characteristics and disease activity. Such results have broad prospects in the treatment of chronic recurrent inflammatory diseases such as psoriasis, including Crohn's disease and rheumatoid arthritis.
Psoriasis is a chronic recurrent T cell mediated inflammatory skin disease. It is characterized by scaly red patches covering the surface of the human body. These plaques are triggered by the cytokines tumor necrosis factor (TNF) and interleukin-23 (IL-23) produced by abnormally activated dendritic cells. These cytokines promote the production of helper T-cell 17 (Th17) cells, releasing the pro-inflammatory cytokines IL-17 and IL-22, which are the pathogenesis of the disease. The elucidation of the immune pathway in the study of psoriasis has led to the use of biological methods to target and inhibit these virulence factors. Biological methods for blocking TNF, Il-23p40 and IL-17 biologics are currently part of the strategy for the treatment of moderate to severe psoriasis. But it has its limitations. Regardless of the clinical activity of the disease, the dosing regimen usually lasts for a long time. Since the target cytokine is also involved in antimicrobial defense, these standard dose regimens result in an increased risk of infection. Designing a flexible anti-inflammatory treatment that relies on specific ways of mitigating and restarting treatment is still a challenge for precision medicine.
Schukur et al. used synthetic biology to accept this challenge. The authors engineered human embryonic kidney cells as cytokine "converter" cells to selectively detect psoriasis inflammatory biomarkers: the combination of tumor necrosis factor and IL-22. In response to this finding, the engineered cells are activated, releasing the cytokines IL-4 and IL-10, inhibiting inflammation, and controlling psoriasis.
The signaling of tumor necrosis factor receptors in metastatic cells controls the expression of the IL-22RA subunit through a synthetic nuclear factor promoter, which is artificially coupled to the signaling pathway of the IL-22 receptor (IL-22R). Thus, when IL-22 is present, detection of TNF initiates the expression of functional Il-22R. The IL-22R signaling pathway initiates the expression of IL-4 and IL-10. Thus, TNF and IL-22 signals are artificially linked to achieve a transition from an anti-inflammatory cell transformed into a transducer cell in a transducer cell.
Schukur et al. examined the therapeutic potential of synthetic cytokine transducer cells in experimental model mice of psoriasis. The transformed cells are encapsulated into a biomaterial based on sodium alginate with the best pore size for cytokine diffusion but lacking immunogenicity. Encapsulated cells were implanted with imiquimod to treat the peritoneum of mice induced by psoriasis. The transducer cells detected a cycle of tumor necrosis factor and IL-22 produced by psoriatic plaques, which reduced the severity of the disease by producing IL-4 and IL-10. Transformer cells can also be activated by psoriasis patients with severe skin disease blood, indicating the therapeutic suitability of the transducer cells in humans. Interestingly, in a prophylactic model, transducer cells were implanted into mice prior to induction of psoriasis, and transducer cells effectively inhibited the development of psoriasis. The transducer cells are highly sensitive and they detect very low concentrations of pro-inflammatory cytokines before they develop into obvious skin conditions.
A major advantage of synthetic cytokine transducer cells is that treatment is unique when inflammation is the source of psoriasis. In fact, irrelevant inflammatory processes, including bacterial or viral infections, cannot be initiated by the inflammatory factors TNF and IL-22. The transducer cells ensure treatment only when the disease is active. In fact, the cell viability of the converter is turned off when TNF and IL-22 are absent. With the addition of TNF and IL-22, the cell viability of the converter is fully restored. Importantly, the input of low levels of pro-inflammatory cytokines produces low levels of anti-inflammatory cytokine output, indicating that the cytokine activity of the transducer cells can be fine-tuned as needed ("on-demand"). The engineered transducer cells also allow for continuous administration of therapeutic doses of anti-inflammatory IL-4 and IL-10. This is a huge advantage over recombinant cytokines that require daily injections with a short half-life.
Future studies identifying other cytokine combinations characterized by chronic relapsing inflammatory disease may be markers of early activity distinguishing disease from an infectious or unrelated inflammatory response. However, many important issues need to be addressed before synthetic transducer cells can enter clinical trials. This includes the type of cell used to synthesize the transducer (most likely autologous cells), whether the heterogeneity of the patient-specific response, the metering, the location of the implant, and the type of encapsulation require recovery. Overcoming these obstacles can lead to tremendous advances in precision medicine and new treatments for psoriasis and other chronic inflammatory diseases.
Source: Bio-Exploration
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