Alemtuzumab mediates the CD 39+ T-regulatory response via CD23 + macrophages

Alemtuzumab (ALM) effectively prevents multiple sclerosis (MS) relapses. It causes lymphocytic depletion with the subsequent enhancement of T-regulatory cell population. Direct administration of ALM to T-cells causes cytolysis. However, the T-cells may be indirectly affected by monocyte derived cells, which are resistant to ALM cytotoxicity. We aimed to examine whether ALM modulates monocytes and whether the crosstalk between monocytes and lymphocytes previously exposed to ALM would result in anti-inflammatory effects. CD14+ monocytes of 10 healthy controls and 10 MS (treatment naive) patients were isolated from peripheral blood mononuclear cells (PBMCs), exposed to ALM, reintroduced to PBMCs depleted from CD14+ cells and then the macrophage profile was taken and T-cells markers were measured. ALM promoted M2 anti-inflammatory phenotype as noted by an increased percentage in the populations of CD23+ , CD83+ and CD163+ cells. CD23+ cells were the highest up regulated (7-fold, P = 0.0002). The observed effect was higher in MS patients as compared with healthy subjects. The ALM- exposed macrophages increased the proportion of T-regulatory cells, without affecting the proportion of T-effector cells. Neutralizing the CD23+ monocyte cells with antibodies reversed the effect specifically on the CD4+ CD39+ T-regulatory cell subpopulation but not on the CD4+ CD25hi CD127lo FOXP3+ subpopulation. ALM induces monocytes' conversion into anti-inflammatory macrophages, which in turn promote T-regulatory enhancement, in a CD23+ dependent manner. These findings suggest the mechanism of action of ALM is relevant to aspects of MS pathogenesis.