Transplantation of Engineered Macrophages Rescues Mice from Sepsis

There are many situations in which it might be advantageous to deliver large numbers of immune cells into a patient, to set them to work as reinforcements for the native immune cell populations. It is technically feasible to grow and then introduce into a patient twice as many – or ten times as many, or even more – of some classes of immune cell as are normally present in the body at any given time. At the moment, therapies of this nature are largely focused on treating cancers, such as the approach pioneered by LIfT Biosciences. That the transferred immune cells come from a donor rather than being generated from a sample of patient cells is actually helpful in terms of their ability to attack a cancer.

For other potential applications, however, it will usually be less helpful to have immune cells from person A introduced into person B. The downsides, in that the immune cells are foreign and can thus attack healthy tissue or spur inflammatory responses from native cells, can outweigh the benefits. Nonetheless, in the research materials noted below, scientists use this approach in the treatment of the later stages of sepsis resulting from infection. This is a life-threatening condition in which older individuals fare far worse than younger individuals. Older patients have a higher risk of sepsis, and lower odds of survival, particularly at the point at which the immune system becomes overwhelmed by a population of pathogens replicating beyond its ability to control.

In a perfect world, it would be possible to generate cost-effective populations of immune cells that can be introduced into any patient as a way to reinforce the immune response for a time. This would either mean a much cheaper approach than presently exists to the production patient-matched cells using reprogramming techniques, or a way to generate cell lines that are not recognized as being foreign to the body, no matter who they are provided to. Approaches to both of these options are at various stages of development in the research community and in biotech companies.

Finding a new way to fight late-stage sepsis

Cells called macrophages are one of the first responders in the immune system, with the job of “eating” invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don’t function as they should. In this study, researchers collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins.

The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to “manufacture” a new therapy.

After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours – and for those with lingering bacteria in the blood, a second treatment cleared them away.

Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis, and thus, alternative therapeutic approaches are urgently needed. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression.

The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.

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