Clinical Trials of Immunomodulation in Ischemic Stroke

Inflammatory mechanisms are currently considered as a prime target for stroke therapy. There is evidence from animal studies that immune signals and mediators can have both detrimental and beneficial effects in particular stages of the disease process. Moreover, several of these mechanisms are turned on with sufficient delay after ischemia onset to make them amenable to therapeutic intervention. Several clinical proof-of concept trials have investigated the efficacy of different immunomodulatory approaches in patients with stroke. Trials targeting the innate immune system have focused on reduction of microglial activation, inhibition of neutrophil migration, and interleukin-1 receptor blockade, suggesting that interleukin-1 receptor blockade may be a promising strategy. Studies aiming at halting T-cell migration have also been undertaken with controversial findings regarding prevention of infarct growth in neuroimaging studies. Consistently, recent proof-of-concept trials targeting lymphocytes with drugs such as natalizumab and fingolimod have yielded some promising results on clinical endpoints, but confirmation in larger trials is needed. At present, the understanding of the role of immune mechanisms in neurorepair and neurodegeneration is limited. Improving long-term brain function by mitigating prolonged neuroinflammation that was triggered by acute brain injury could be a strategy in addition to neuroprotection.