Cargando…

2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis

OBJECTIVES/SPECIFIC AIMS: The overall objective of this proposal is to establish and modulate the inflammatory profile of individuals across the spectrum of multiple sclerosis (MS), with a focus on determining the potential of interleukin 4-induced protein 1 (IL4I1) as a possible marker of progressi...

Descripción completa

Detalles Bibliográficos
Autores principales: Davis, Stephanie, Huang, Jeffrey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801836/
http://dx.doi.org/10.1017/cts.2017.21
_version_ 1783460671414861824
author Davis, Stephanie
Huang, Jeffrey
author_facet Davis, Stephanie
Huang, Jeffrey
author_sort Davis, Stephanie
collection PubMed
description OBJECTIVES/SPECIFIC AIMS: The overall objective of this proposal is to establish and modulate the inflammatory profile of individuals across the spectrum of multiple sclerosis (MS), with a focus on determining the potential of interleukin 4-induced protein 1 (IL4I1) as a possible marker of progression and modulator of inflammation in human blood samples. METHODS/STUDY POPULATION: The proposed experimental approach involves isolating plasma and peripheral blood mononuclear cells (PBMCs) from individuals across the spectrum of MS phenotypes, and analyzing these samples primarily by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) methods. Specifically, study groups include: (1) actively relapsing-remitting MS (a-RRMS), (2) non-actively relapsing-remitting MS (n-RRMS), (3) non-active secondary-progressive MS (SPMS), (4) other autoimmune diseases (OAD), (5) healthy controls (HC). RESULTS/ANTICIPATED RESULTS: We expect that IL4I1 treatment increases regulatory cytokine (eg, IL10, TGFb) expression while decreasing Th1 and Th17-derived cytokines (IFNg, IL17), as well as increasing relative composition of regulatory cells (Th2, Treg, M2) as compared with Th1, Th17, M1 (aim 1). Preliminary data on healthy control cells support this prediction. Our central hypothesis is that IL4I1 level indicates the body’s ability to repair itself. As such, we anticipate that all MS groups are deficient in IL4I1, to varying degrees, such that HC>n-RRMS>a-RRMS>SPMS. HC have full repair capacity. RRMS>SPMS as remission indicates existent repair capacity, which is lost in SPMS. n-RRMS>a-RRMS since both, as RRMS, capable of repair response, but a-RRMS triggered this response more recently in response to more recent relapse. In all groups, we expect IL4I-treatment to mitigate inflammation (aim 2). Finally, we expect that H(2)O(2) production by IL4I1 is a key player in IL4I1 function, and that H2O2 will preferentially induce oxidative stress to pro-inflammatory subsets of PBCMs (aim 3). DISCUSSION/SIGNIFICANCE OF IMPACT: MS is a chronic inflammatory neurodegenerative disease of the central nervous system that, with an average age of onset of 34, afflicts over 2.3 million individuals worldwide during many of the most productive years of their lives. The pathogenesis of MS, which involves autoimmune destruction of myelin, is poorly understood. Accurate biomarkers, which could predict disease progression, are yet to be identified and would provide valuable information to patients and their treating clinicians. Likewise, effective treatments are few and in high demand. IL4I1 is a promising candidate for both roles.
format Online
Article
Text
id pubmed-6801836
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Cambridge University Press
record_format MEDLINE/PubMed
spelling pubmed-68018362019-10-28 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis Davis, Stephanie Huang, Jeffrey J Clin Transl Sci Basic Science/Methodology OBJECTIVES/SPECIFIC AIMS: The overall objective of this proposal is to establish and modulate the inflammatory profile of individuals across the spectrum of multiple sclerosis (MS), with a focus on determining the potential of interleukin 4-induced protein 1 (IL4I1) as a possible marker of progression and modulator of inflammation in human blood samples. METHODS/STUDY POPULATION: The proposed experimental approach involves isolating plasma and peripheral blood mononuclear cells (PBMCs) from individuals across the spectrum of MS phenotypes, and analyzing these samples primarily by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) methods. Specifically, study groups include: (1) actively relapsing-remitting MS (a-RRMS), (2) non-actively relapsing-remitting MS (n-RRMS), (3) non-active secondary-progressive MS (SPMS), (4) other autoimmune diseases (OAD), (5) healthy controls (HC). RESULTS/ANTICIPATED RESULTS: We expect that IL4I1 treatment increases regulatory cytokine (eg, IL10, TGFb) expression while decreasing Th1 and Th17-derived cytokines (IFNg, IL17), as well as increasing relative composition of regulatory cells (Th2, Treg, M2) as compared with Th1, Th17, M1 (aim 1). Preliminary data on healthy control cells support this prediction. Our central hypothesis is that IL4I1 level indicates the body’s ability to repair itself. As such, we anticipate that all MS groups are deficient in IL4I1, to varying degrees, such that HC>n-RRMS>a-RRMS>SPMS. HC have full repair capacity. RRMS>SPMS as remission indicates existent repair capacity, which is lost in SPMS. n-RRMS>a-RRMS since both, as RRMS, capable of repair response, but a-RRMS triggered this response more recently in response to more recent relapse. In all groups, we expect IL4I-treatment to mitigate inflammation (aim 2). Finally, we expect that H(2)O(2) production by IL4I1 is a key player in IL4I1 function, and that H2O2 will preferentially induce oxidative stress to pro-inflammatory subsets of PBCMs (aim 3). DISCUSSION/SIGNIFICANCE OF IMPACT: MS is a chronic inflammatory neurodegenerative disease of the central nervous system that, with an average age of onset of 34, afflicts over 2.3 million individuals worldwide during many of the most productive years of their lives. The pathogenesis of MS, which involves autoimmune destruction of myelin, is poorly understood. Accurate biomarkers, which could predict disease progression, are yet to be identified and would provide valuable information to patients and their treating clinicians. Likewise, effective treatments are few and in high demand. IL4I1 is a promising candidate for both roles. Cambridge University Press 2018-05-10 /pmc/articles/PMC6801836/ http://dx.doi.org/10.1017/cts.2017.21 Text en © The Association for Clinical and Translational Science 2018 http://creativecommons.org/licenses/by/4.0/ This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic Science/Methodology
Davis, Stephanie
Huang, Jeffrey
2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title_full 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title_fullStr 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title_full_unstemmed 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title_short 2109: Interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
title_sort 2109: interleukin 4-induced protein 1 as a biomarker and treatment option in multiple sclerosis
topic Basic Science/Methodology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801836/
http://dx.doi.org/10.1017/cts.2017.21
work_keys_str_mv AT davisstephanie 2109interleukin4inducedprotein1asabiomarkerandtreatmentoptioninmultiplesclerosis
AT huangjeffrey 2109interleukin4inducedprotein1asabiomarkerandtreatmentoptioninmultiplesclerosis