Whilst we talk about targeted B cell treatments, alemtuzumab possibly is what I’d term a ‘Domestos’ style drug. This type of drug is useful when your aim is to control the entire immune system quickly. Drugs similar to this are cyclophosphamide, cysclosporin and mitoxantrone; which are all considered highly active therapies.
Many of you know alemtuzumab as an anti-CD52. CD52 is found on the surface of mature T- and B-cells, circulating monocytes, macrophages and circulating dendritic cells. So giving an anti-CD52 has an effect on all of these cell types. The effect on the T- and B-cells is quick, with counts dropping to almost undetectable by day 7 by a process of celluar lysis. Following this there seems to be a relative increase in the anti-inflammatory regulatory T-cell pool. These T cells are purported to be the reason for the long-lasting effect of the drug on MS (with most individuals not requiring re-treatment for 4 years).
But, a recently published piece of research also shows that alemtuzumab has off shoot effects on the macrophage pool. This is because the immune system cross-talks. Treating with alemtuzumab appears to promote differentiation of monocytes into anti-inflammatory M2 macrophages, which in turn enhances the regulatory T-cell population. The two then sit in a positive feedback loop promoting the differentiation of each.
For those who have already benefited from alemtuzumab treatment, this research is a helpful addition. It also points to why certain treatments only need to be used as induction treatments with a few infusions rather than as maintenance treatment with regular treatment.
Immunol Cell Biol 2020 Dec 11. doi: 10.1111/imcb.12431. Online ahead of print.
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 naïve) 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.