Abstract
ObjectivesDendritic cells (DCs) serve a critical role both in promoting and inhibiting adaptive immunity. The goal of this study was to investigate the effect of natalizumab (NTZ) treatment on DC numbers, phenotype, and function in patients with multiple sclerosis (MS).MethodsFrequency and phenotype of myeloid and plasmacytoid DCs (MDCs and PDCs, respectively) were analyzed in blood from two separate cohorts of untreated, interferon-treated, or NTZ-treated MS patients. In addition, PDCs were stimulated with CpG-containing oligonucleotides or co-cultured with homologous T cells in the presence or absence of NTZ in vitro to determine functional effects of NTZ treatment.ResultsWe observed that NTZ treatment was associated with a 25–50% reduction in PDC frequency in peripheral blood as compared to untreated MS patients, while the frequency of MDCs was unchanged. PDCs in NTZ-treated patients displayed a mature, activated phenotype with increased expression of HLA-DR, TLR9, CCR7, IL-6 and IL-12. In contrast, in vitro treatment with NTZ did not increase markers of PDC activation or their ability to induce T cell differentiation.ConclusionOur study shows that NTZ treatment is associated with a reduced frequency of PDCs in the peripheral circulation, but that PDCs in NTZ-treated individuals display an activated phenotype. Taken together the data suggests that transmigration of activated PDCs is preferentially affected by blockade of integrin α4 leading to an increased frequency of activated PDCs in blood.
Highlights
Natalizumab (NTZ) is a humanized monoclonal antibody against the a4 subunit (CD49d) of the a4b1 (VLA-4) and a4b7 integrins that has been approved for the treatment of multiple sclerosis (MS) due to its ability to reduce disease activity and severity in patients with relapsing-remitting MS (RRMS) [1]
Integrin a4 is expressed by Dendritic cells (DCs) [12] and preliminary studies indicate that NTZ treatment in MS is associated with changes in DC trafficking as evidenced by a potential reduction in the frequency of circulating plasmacytoid DCs (PDCs) and in the number of CD209+ DCs in the perivascular spaces of the brain [13,14]
Patients treated with NTZ had roughly 25% less PDCs in peripheral blood (0.7260.30%) compared to untreated patients (1.0460.53%) in our first cohort of 75 patients (p = 0.03; Fig. 1A– B)
Summary
Natalizumab (NTZ) is a humanized monoclonal antibody (mAb) against the a4 subunit (CD49d) of the a4b1 (VLA-4) and a4b7 integrins that has been approved for the treatment of multiple sclerosis (MS) due to its ability to reduce disease activity and severity in patients with relapsing-remitting MS (RRMS) [1]. Previous studies have shown that NTZ treatment in MS is associated with increased frequencies of activated CD4+ T cells producing proinflammatory cytokines such as IFN-c, TNF, and IL-17 in peripheral blood [2,3,4,5]. Such effects of NTZ are, not limited to activated CD4+ T cells, but an increase in peripheral blood frequencies of total T cells, B cells, and NK cells has been demonstrated, while frequencies of monocytes were decreased [6,7,8,9]. Antigen-presenting cells (including DCs) in the cerebral perivascular spaces are believed to be continuously replaced by cells migrating from peripheral blood and it is plausible that the observed reduction in DC numbers is due to impaired migration of DCs from peripheral blood [15,16]
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