New immune targets to improve survival from sepsis

Morales-Mantilla, Daniel; Parihar, Robin; King, Katherine

article

New immune targets to improve survival from sepsis

In a pre-clinical study, researchers from the US set out to develop a treatment for sepsis. Here, Daniel Morales-Mantilla, Dr Robin Parihar and Dr Katherine King, from Baylor College of Medicine, describe how they utilised haematopoietic stem and progenitor cell infusion to improve the survival of mice from sepsis.

Sepsis accounts for up to 20 percent of deaths worldwide and one in three hospital deaths.¹ Despite being a major global health concern, how to best treat sepsis is an area of active research and there remains a need for new therapeutic approaches to improve sepsis outcomes.

Though initiated by an infection process, sepsis is truly an immune phenomenon. While pathogens themselves can cause direct damage to tissues and organs, it is often the host immune system that drives organ damage and failure.^2,4,6-9 Sepsis is characterised by a dysregulated immune response to infection, in which very high levels of pro-inflammatory signals disrupt circulation and cause multiorgan tissue damage.^2,3 The longer the immune system stays overstimulated and overactivated, the less efficient the host becomes in fighting the infection, and damage to vital organs ensues.^2-5 Thus, targeting key immune components that influence immune dysregulation during sepsis could serve as a new therapeutic approach to restoring balance, reducing hyperinflammation and preventing morbidity and mortality.

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Cell therapies have shown great potential and proved to be effective against a variety of diseases such as stroke, diabetes mellitus and cancer.^18-20,21-23 Currently, granulocyte infusions from allogeneic sources are used as a cellular therapy for neutropenic patients with sepsis.^42-47 Patients are typically given ~1×1010 granulocytes per m² body surface area daily or every other day. Unfortunately, clinical outcomes from granulocyte transfusions have been mixed and the high number of cells and the frequency at which they are required are significant practical limitations.^42-44,46,47 Immune cells, including granulocytes, are derived from haematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), together called haematopoietic stem and progenitor cells (HSPCs) in the bone marrow. As HSPCs can directly recognise proinflammatory signals that drive their activation and stimulate them to produce more immune cells,^10-13 we set out to determine their potential for cell therapy against sepsis.

In our recent pre-clinical study, we found that infusion of 10,000 HSPCs from a healthy donor – less than 0.01 percent of the available bone marrow – can improve survival from sepsis.¹⁴ For these studies, we used a mouse model of Streptococcus pyogenes myositis. S. pyogenes, also known as Group A Streptococcus (GAS), is a bacterium that causes sepsis in people and is fatal in mice in the period of five to seven days. GAS-infected mice showed a massive mobilisation of myeloid cells into the circulation and a concomitant depletion of HSPCs from the bone marrow. Lineage tracing experiments showed that endogenous HSPCs produced new immune cells of the myeloid lineage during this sepsis response, including neutrophils and macrophages critical in phagocytosing and killing bacteria.

Compared to mock-treated controls, mice infused with HSPCs had restored HSPC numbers in the bone marrow, lower signs of morbidity and increased overall survival. An advantage of HSPC infusion over granulocyte infusion is that HSPCs have excellent expansion potential and a much longer lifespan than granulocytes, which live for only two to three days in the allogeneic setting.^48,49 Despite the ability of infused HSPCs to expand and restore cell populations in the infected animals, to our surprise, HSPC infusion had no impact on pathogen clearance, as infected mice had the same bacterial burden regardless of whether they had received HSPC infusion. Instead, HSPC infusion led to a dramatic increase in immune-regulatory cells of the myeloid lineage called myeloid-derived suppressor cells (MDSCs),^24-27 which dampen inflammation by suppressing inflammatory cytokines. Notably, the proinflammatory cytokines IL1, IL6, IL8, TNFa, interferons and MIP1a were reduced in mice that received HSPC infusion. These cytokines are key drivers of morbidity during sepsis and contribute to systemic inflammatory response syndrome, including fever, tachypnea, vasodilation and circulatory collapse.^28,29 Our findings show that HSPC infusion improves survival by dampening maladaptive proinflammatory signalling during sepsis.

While there is accumulating evidence that HSPCs play an active role in recognising immunological stress,^{11,13,15,16,30-41} our study represents the first demonstration that HSPCs can make a direct impact on immunity and immune regulation. Proof that HSPCs can directly influence the outcome of severe infections and sepsis by reducing hyperinflammation opens innumerable possibilities for the use of HSPCs as therapeutic cells. Furthermore, the dose of 10,000 HSPCs used in our study is equivalent to only 1.7×107 cells per m2 body surface area and represents less than 0.01 percent of the nucleated bone marrow cells in a mouse. Evidence that a small number of HSPCs could confer similar or more robust protection than granulocyte therapy addresses a significant practical limitation in current cell therapy for sepsis.

Use of HSPCs as cell therapy for sepsis has a few practical considerations that remain to be addressed. First, HSPC infusion could lead to concerns for long-term complications like graft versus host disease (GVHD). The mix of HSPCs used in our study does contain long-term engrafting HSCs but is largely comprised of MPPs, which have a lifespan of weeks but no long-term self-renewal capacity. Human HSPCs are easily obtainable from buffy coats or from cord blood of healthy donors and differential expression of CD90 and CD49f makes it feasible to differentiate between HSCs and MPPs. We speculate that use of a selected population of MPPs could improve outcomes from sepsis while alleviating concerns about GVHD. Furthermore, methods to recruit or cultivate MPPs for therapeutic use are in development and would enable creation of large numbers of MPPs as a renewable therapeutic resource. Induced pluripotent stem cells (iPSCs) are also a promising tool to produce specific cells such as MPPs for use as an off-the-shelf cell therapy.⁵¹

Our study demonstrated that HSPC infusion improved survival of mice from sepsis by restoring MDSCs to reduce systemic inflammation. Therefore, whether infusion of HSPCs or infusion of MDSCs would be the most effective approach to treat sepsis is worth considering. MDSCs have strong anti-inflammatory mechanisms that can be expected to immediately dampen inflammation.^24,26,27,51 The strong anti-inflammatory functions of MDSCs, however, can be a double‑edged sword depending on the setting. In our sepsis model, MDSCs contributed to prevention of inflammation‑driven mortality by reducing systemic cytokine levels. However, some studies have shown that MDSCs also can contribute to infection persistence and clinical worsening during sepsis.²⁴ In contrast, MPPs are long-lived multipotent progenitors with a greater proliferative and differentiation capacity than MDSCs.^49,50 These cells would be expected to exert their effects more gradually but could persist for longer than infused MDSCs. It remains to be determined if a fast-acting anti-inflammatory response induced by MDSC infusion or a longer lasting MPP-based cell therapy would more efficiently prevent sepsis‑related death. Overall, novel cell-based approaches to reduce morbidity and mortality by regulating hyperinflammation are promising avenues in the future of sepsis treatment.

About the authors

Daniel Morales-Mantilla is an immunologist whose work focuses on the role of haematopoietic stem and progenitor cells in immune responses against infectious diseases. Currently, he is working with Dr Katherine King in developing a cell therapy to increase survival from sepsis.

Dr Robin Parihar is a paediatric oncologist who cares for children with solid tumours. His research lab is interested in stimulating the immune system to fight paediatric solid tumours with a specific type of immune cell called the natural killer (NK) cell. Current projects aim to enhance NK cell function by genetic modification to target suppressive myeloid cells of the tumour microenvironment called inhibitory macrophages (M2-TAMs) or myeloid-derived suppressor cells (MDSCs).

Dr Katherine King is Associate Professor of Pediatric Infectious Diseases at Baylor College of Medicine, where she is part of the faculty for the Stem Cells and Regenerative Medicine Center and serves as a co-director of the Baylor Medical Scientist Training Program and Associate Vice-Chair for Research for the Department of Pediatrics. She received her MD and PhD degrees from Washington University in St Louis. A board-certified paediatrician within the Infectious Disease Division, Katherine’s research focuses on the molecular mechanisms by which inflammation affects blood and immune cell production and clonal competition by haematopoietic stem cells in the bone marrow.

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