Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis

Abstract

Objective:To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.Methods:Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined.Results:In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change.Conclusions:Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS.

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

“…There has been evidence that, in addition to its previously known effects of depleting and repopulating T and B lymphocytes, alemtuzumab treatment could also result in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS [43][44][45][46][47][48]. These lines of evidence help to explain the recent long-term efficacy data from the Phase II/III extension study with up to 6 years of treatment (2 years of the core study plus 4 years of the extension).…”

“…In CAMMS223, blood samples for PK were collected in 19 patients treated at a single study site. Samples were to be collected during and after each treatment course at months 0, 12 and 24; specifically at 0, 4,8,24,28,32,48,52,56,72,76,80,96, 100 and 104 h post-dose (relative to the first dose of a treatment course) during week 1, and once at weeks 1, 2, 3 and 4 after the last dose of a treatment course.…”

Enhancing natural killer cells is beneficial in multiple sclerosis – Commentary

“…5,[7][8][9] As underscored in the commentary by Dr Laroni, an interest in NK cells as regulators of the human disease was rekindled by mechanistic substudies of MS clinical trials that revealed an association between the therapeutic efficacy of disease-modifying therapies (DMTs), or autologous hematopoietic stem cell transplantation, and the expansion of circulating NK cells. 7,[10][11][12][13] Of particular interest is a CD56 bright subset of NK cells that were first found to accumulate in the blood of MS patients treated with daclizumab, and subsequently in patients treated with alemtuzumab or dimethyl fumarate. [10][11][12] While compelling, these studies do not definitively distinguish between whether NK cell expansion plays a causative role in MS disease suppression or represents an epiphenomenon.…”

From brain to brawn

“…The underlying mechanisms resulting in these effects include complement-dependent cell lysis, antibodydependent cellular cytotoxicity, and apoptosis leading to elimination of T cells. However, the effect of alemtuzumab on innate cells has been less investigated in patients with RRMS, and this is the main goal of the study of Gross et al 1 Innate immune cells comprise myeloid cells such as dendritic cells (DCs) and macrophages and lymphoid cells (ILCs), which include cytotoxic natural killer (NK) cells and 3 noncytotoxic tissue-resident subsets: ILC1, ILC2, and group 3 ILC (ILC3 and tissue-induced cells). The authors studied 12 patients with RRMS before and during alemtuzumab treatment and examined the effects on several of the above innate cell populations.…”

“…The findings suggest that myopathy with HMGCR antibodies may occur with myositis without necrotizing features, and confirm that these antibodies not only occur with statin exposure but also as a paraneoplastic manifestation of cancer. 1 In another study, Miller et al 5 investigated the prevalence of autoimmune disease in symptomatic C9ORF72 (C9) mutation carriers and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts. The authors previously reported a relationship between systemic autoimmune inflammation in FTD progranulin (PGRN) mutation carriers and semantic variant primary progressive aphasia (svPPA) patients.…”