Â鶹´«Ã½Ó³»­

Â鶹´«Ã½Ó³»­

Explore the latest content from across our publications
Join The Â鶹´«Ã½Ó³»­

Log In

Forgot Password?
Create New Account

Loading... please wait

Abstract Details

Interrogating the Influence of the Multiple Sclerosis Modifying Drug Cladribine (2-Chlorodeoxyadenosine) Upon Primary Human Monocytes and Macrophages
Multiple Sclerosis
P7 - Poster Session 7 (5:30 PM-6:30 PM)
9-004
To demonstrate the immunomodulatory effect of Cladribine upon human monocytes, monocyte-derived macrophages (MDMs), and microglia.
Cladribine, a synthetic purine nucleoside analogue, is an effective disease-modifying drug for multiple sclerosis (MS). It induces cell death, particularly of lymphocytes, and leads to long-lasting drug-free remission, potentially attributable to immune reconstitution. Additionally, Cladribine has immunomodulatory effects on innate cells, such as dendritic cells and monocytes, which could also contribute to its efficacy. However, whether Cladribine modulates human macrophage polarization or monocyte differentiation is unknown.
We analysed the phenotype and differentiation of monocytes from MS patients (n=10) receiving their first course of oral Cladribine (Mavenclad®), at the recommended cumulative dose of  3.5 mg/kg over 2 years, both before and 19-21 days after treatment commencement. We further investigated the direct effects of Cladribine in vitro using human adult primary MDMs (6 days treatment, during differentiation with GM-CSF and/or M-CSF) and microglia. 
Flow cytometry analysis of monocytes from MS patients undergoing Cladribine treatment revealed that the proportion of monocyte subsets (based on CD14/CD16 experession) remained unchanged after treatment commencement. Furthermore, RT-qPCR and flow cytometry analysis revealed that M-CSF-differentiated MDMs from such patients, after Cladribine treatment commencement, showed a slight reduction in the expression of the proinflammatory cytokine TNF (1.34 fold-change, p=0.0078) but no significant change in IL1B, CD40, IL10, MERTK, CD80 or CD163 expression. In vitro-generated MDMs treated 6 days with Cladribine (0.05 mM) showed increased expression of costimulatory molecules CD80 and CD40 (GM-CSF-differentiated MDMs), as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK (M-CSF-differentiated MDMs), depending on the differentiation conditions. In vitro-treated primary human adult microglia samples are under analysis for gene expression and cell viability.
The results from this ongoing study suggest that, even though Cladribine treatment does not affect the monocyte subsets proportion, Cladribine can affect MDM differentiation and cytokine production.
Authors/Disclosures

PRESENTER 		No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Trevor J. Kilpatrick, MBBS, PhD (Melbourne Neuroscience Institute, University of Melbourne) Dr. Kilpatrick has received stock or an ownership interest from Mx3 diagnostics. The institution of Dr. Kilpatrick has received research support from NHMRC. The institution of Dr. Kilpatrick has received research support from NMSS. The institution of Dr. Kilpatrick has received research support from MSRA. Dr. Kilpatrick has received intellectual property interests from a discovery or technology relating to health care. Dr. Kilpatrick has received publishing royalties from a publication relating to health care.