Table 1.

Immunomodulating therapies to prevent stroke-associated pneumonia and infections

Mechanism of action	Reference	Drug	Time of administration	Type of study	Major findings
Inhibition of the SNS	Prass et al. 2003 [18]	Propanolol	Immediately before and also 4 and 8 h after MCAO.	Experimental (MCAO mice)	Prevention of lymphocyte apoptosis, lymphopenia, monocytic deactivation and changes in lymphocyte cytokine production; prevention of bacteremia and pneumonia; ↑ survival rates
	Wong et al. 2011 [33]	Propanolol and 6-OHDA	24 h after MCAO	Experimental (MCAO mice)	Reversion of the iNKT cell phenotype induced by MCAO; ↑ survival rates; ↓ bacterial load in blood, lungs, liver, and spleen
	Yan and Zhang 2014 [19]	Propanolol	Immediately before and also 4 and 8 h after MCAO.	Experimental (MCAO mice)	↓ serum levels of MN, NMN and IL-10; ↑ pro-inflammatory cytokines; ↑ spleen volume
	Deng et al. 2016 [79]	6-OHDA	3 days before MCAO	Experimental (MCAO rats)	Reversion of the expression of MHC class II; ↑ TNF-a and IFN-γ levels in LPS-stimulated macrophages in vitro; ↓ NF-κB activation; ↑ β-arrestin2 expression
	Sykora et al 2015 [80]	β1-selective BBs, nonselective BBs	Before and after stroke	Clinical	↓ frequency of pneumonia; association of post-stroke BB treatment with mortality
	Maier et al. 2015 [81]	BBs (mainly metoprolol and bisoprolol)	Before and after stroke	Clinical	No differences in the risk of pneumonia; ↓ mortality.
	Maier et al. 2018 [82]	BBs	Before and after stroke	Clinical	No differences in the rates of pneumonia nor mortality
Inhibition of the HPA axis	Prass et al. 2003 [18]	RU486	24 h, 5 h, and immediately before MCAO	Experimental (MCAO mice)	Prevention of lymphocyte apoptosis, lymphopenia, and monocytic deactivation
Immunomodulation of iNKT cells	Wong et al. 2011 [33]	α-GalCer	24 h after MCAO	Experimental (MCAO mice)	↑ systemic levels of IFN-γ; ↓ stroke-induced neutrophil pulmonary influx and lung edema; ↓ bacterial load in blood, lungs, liver and spleen
Inhibition of CD147	Jin et al. 2019 [83]	CD147 antibody	4 h after MCAO	Experimental (MCAO mice)	↓ lung damage; ↓ lung leukocyte infiltration; ↓ plasma and lung IL-17A
Inhibition of PTEN	Guan et al. 2013 [84]	Bvp	24 h after MCAO	Experimental (MCAO mice)	↓ bacterial loads in lung of bpv-treated mice; restoration of akt activation in the lung; ↓ mortality
GM-CSF	Dames et al. 2018 [85]	Recombinant mGM-CSF	6, 30, and 54 h after MCAO	Experimental (MCAO mice)	↑ leukocyte counts in lung; ↑ WBC count; ↑ long-term outcome

Experimental and clinical studies are represented in this table. In the Major findings column, all the results are referred to the patients or animals treated with the immunomodulator agent in comparison with their respective non-treated controls. MCAO middle cerebral artery occlusion, NA non-annotated, 6-OHDA 6-hydroxydopamine, iNKT invariant natural killer T cells, NM metanephrine, NMN normetanephrine, IL-10 interleukin-10, MHC major histocompatibility complex, TNF-α tumor necrosis factor-α, IFN-γ interferon-γ, LBP lipopolysaccharide binding protein, BB beta blocker, α-GalCer α-Galactosylceramide, Bvp bisperoxovanadium, GM-CSF granulocyte-macrophage colony-stimulating factor