Autologous M2-like macrophage applications in children with cerebral palsy

Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.