Immunotherapy With Antiprogrammed Cell Death 1 Antibody Improves Outcome in a Mouse Model of Spinal Cord Injury Followed by Staphylococcus aureus Pneumonia.OBJECTIVES
 In patients with spinal cord injury, spinal cord injury-immune depression syndrome induces pneumonia.  We aimed to develop a new spinal cord injury-immune depression syndrome mouse model and to test antiprogrammed cell death 1 therapy.


 Research laboratory.


 SUBJECTS
 RjOrl: SWISS and BALB/cJ mice.


 Mouse model of spinal cord injury-immune depression syndrome followed by a methicillin-susceptible Staphylococcus aureus pneumonia.  Lung injuries were assessed by histologic analysis.  Membrane markers and intracytoplasmic cytokines were assessed by flow cytometry.  Cytokine production was assessed by quantitative polymerase chain reaction (messenger RNA) and enzyme-linked immunosorbent assay (protein).  Animals were treated with blocking antiprogrammed cell death 1 antibodies (intraperitoneal injection).


 Spinal cord injury mice were more susceptible to methicillin-susceptible S. aureus pneumonia (increased mortality rate).  An early inflammatory response was observed in spinal cord injury mice characterized in lungs by a decreased percentage of aerated tissue, an increased production of proinflammatory cytokines (tumor necrosis factor-α).  In spleen, an increased expression of major histocompatibility complex class II molecules on dendritic cells, and an increased production of proinflammatory cytokines (interleukin-12, interferon-γ) was observed.  Following this pulmonary and systemic inflammation, spinal cord injury-immune depression syndrome was observed in spleens as acknowledged by a decrease of spleen's weight, a lymphopenia, a decrease of major histocompatibility complex class II expression on dendritic cells.  An increase of interleukin-10 production and the increase of a cell exhaustion marker expression, programmed cell death 1 receptor on T-cell were also observed.  Blockade of programmed cell death 1 molecules, improved survival of spinal cord injury infected mice and enhanced interferon-γ production by natural killer T cells as well as number of viable CD4 T cells.


 CONCLUSIONS
 This model of spinal cord injury in mice mimics a clinical scenario rendering animals prone to a secondary pneumonia.  We show for the first time an acute T-cell exhaustion-like phenomenon following an initial inflammatory response.  Finally, inhibition of exhaustion pathway should be considered as a new therapeutic option to overcome spinal cord injury-immune depression syndrome and to decrease the rate of nosocomial pneumonia.
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