Table 1.

Therapeutic interventions targeting brain–peripheral immune communications in clinical studies.

Intervention	Mechanism	Study design	Results	References
Fingolimod	Inhibit inflammatory	Open-label, evaluator-blinded, parallel-group	Oral fingolimod was safe within 72 h of stroke onset;	(121)
	T-lymphocyte infiltration	Clinical pilot trial	Oral fingolimod reduced secondary tissue injury and microvascular permeability, attenuated neurological deficits, and promoted recovery
		Randomized, open-label, evaluator-blind, multicenter pilot trial	Combination therapy of fingolimod and alteplase reduced reperfusion injury, improved clinical outcomes, and was tolerated in acute ischemic stroke patients	(122)
Etanercept	Reduce TNF secretion	Phase I/II parallel double-blind randomized controlled clinical trial	Peri-spinal etanercept promoted mobility of paretic arm and alleviated pain in chronic stroke	(123)
Minocycline	Microglia polarization	Systematic review and meta-analysis	Minocycline improved functional recovery in acute stroke patients	(124)
		Exploratory trial	Combining minocycline with tPA lowered plasma matrix metalloproteinase-9 level	(125)
		Single-blind (outcomes assessor) phase I/II controlled clinical trial	Intra-arterial BMNC transplantation between day 5 and 9 after stroke elevated GM-CSF and PDGF-BB levels, lowered MMP-2 level, showed better functional outcome	(126)
		Open-label, single-arm phase I/II study	Surgical transplantation of bone marrow–derived mesenchymal stem cells was safe and related with improved clinical outcome	(127)
BMNCs	Anti-inflammatory, neurotrophic	phase II, multicenter, parallel group, randomized trial with blinded outcome measure	Bone marrow mononuclear stem cells transplanted intravenously after stroke at a median of 18.5 days were safe but showed no beneficial effects for recovery	(128)
		Randomized, double-blind, placebo-controlled, phase 2 trial	Intravenous bone marrow-derived multipotent adult progenitor cells were safe in acute stroke patients but no significant functional improvement was found	(129)
G-CSF	Bone marrow stem cells	Meta-analysis	G-CSF did not improve neurological outcome in stroke patients	(130)
M2 macrophage		Prospective phase I/II nonrandomized open-label clinical study	Intrathecal M2 macrophage therapy was safe and promoted neurological recovery	(131)