Differential monocytic response patterns to MIS416 in vitro during progressive multiple sclerosis and the involvement of NF-kB
ECTRIMS Online Library. Beyers C. 09/13/19; 278688; P1649
Carl Beyers
Carl Beyers
Contributions
Abstract

Abstract: P1649

Type: Poster Sessions

Abstract Category: Poster Session 3

C. Beyers1, G. Webster2, A. La Flamme1,3

1Victoria University of Wellington, Wellington, 2Innate Immunotherapeutics, Auckland, 3Malaghan Institute of Medical Research, Wellington, New Zealand

Central nervous system, but not peripheral immune cell activation, is believed to drive progressive disease during multiple sclerosis (MS). To understand if and how the peripheral innate immune response was altered during progressive MS (pMS), we used the innate immune activator, MIS416, to profile innate immune activation in monocytes. MIS416 is a microparticle that must be phagocytosed to activate its TLR9 and NOD2 targets, and induce IL-1β, IL-10, TNFα, and INFγ production by human PBMC. We found that baseline NF-kB (p65) and STAT1 activity was significantly decreased in monocytes from pMS participants compared to healthy controls, and that MIS416 further reduced the activity of these transcription factors (TF). Additionally, TNFα appeared to be constitutively increased in pMS, and we observed MIS416 to be a strong inducer of both pro- and anti-inflammatory cytokines following in vitro treatment, likely mediated through STAT signalling. Furthermore, we observed that IkB mutations were associated with altered innate immune responses (i.e. TF and cytokines), in in vitro-treated monocytes and serum cytokines from MIS416-treated participants from the same clinical trial cohort. These findings support a central role for NF-kB pathway mutations in regulating monocyte responses to MIS416. Overall, this work indicates that MIS416 therapy has the potential to modulate peripheral immune responses through substantive TF and cytokine induction, which can alter the immune milieu following in vivo treatment.
Disclosure: Nothing to declare.

Abstract: P1649

Type: Poster Sessions

Abstract Category: Poster Session 3

C. Beyers1, G. Webster2, A. La Flamme1,3

1Victoria University of Wellington, Wellington, 2Innate Immunotherapeutics, Auckland, 3Malaghan Institute of Medical Research, Wellington, New Zealand

Central nervous system, but not peripheral immune cell activation, is believed to drive progressive disease during multiple sclerosis (MS). To understand if and how the peripheral innate immune response was altered during progressive MS (pMS), we used the innate immune activator, MIS416, to profile innate immune activation in monocytes. MIS416 is a microparticle that must be phagocytosed to activate its TLR9 and NOD2 targets, and induce IL-1β, IL-10, TNFα, and INFγ production by human PBMC. We found that baseline NF-kB (p65) and STAT1 activity was significantly decreased in monocytes from pMS participants compared to healthy controls, and that MIS416 further reduced the activity of these transcription factors (TF). Additionally, TNFα appeared to be constitutively increased in pMS, and we observed MIS416 to be a strong inducer of both pro- and anti-inflammatory cytokines following in vitro treatment, likely mediated through STAT signalling. Furthermore, we observed that IkB mutations were associated with altered innate immune responses (i.e. TF and cytokines), in in vitro-treated monocytes and serum cytokines from MIS416-treated participants from the same clinical trial cohort. These findings support a central role for NF-kB pathway mutations in regulating monocyte responses to MIS416. Overall, this work indicates that MIS416 therapy has the potential to modulate peripheral immune responses through substantive TF and cytokine induction, which can alter the immune milieu following in vivo treatment.
Disclosure: Nothing to declare.

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