Contributions
Abstract: P997
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Interleukin (IL)-17-producing CD4+ T helper (Th)17 cells are considered key mediators of early MS activity. However, depending on the species and inflammatory milieu, Th17 populations are highly polyfunctional, as reflected by their (co-)production of interferon-gamma (IFN-γ) and granulocyte macrophage colony-stimulating factor (GM-CSF). We performed cross-sectional and longitudinal analyses to refine Th17 effector function in different clinical subgroups of MS. Blood and/or CSF samples were assessed from 60 treatment-naive relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS) patients, and from 17 natalizumab-treated RRMS patients (pre- and both 6m and 12m post-treatment). CIS patients either obtained a second clinical attack within 1 year (CIS-CDMS; n=16) or did not experience subsequent attacks for more than 5 years of follow-up (CIS-CIS; n=16). IFN-γ- and GM-CSF-producing (Th1-like) and not IL-17-producing (classical) Th17 effector memory cells in blood were significantly reduced in CIS-CDMS compared to CIS-CIS (p< 0.01) and healthy control (p< 0.01) groups, as determined by 15-parameter flow cytometry. Similar reductions were found in RRMS blood (p< 0.0001). In the CSF of CIS and RRMS patients, Th1-like Th17 effector memory cells were more abundant and produced higher levels of IFN-γ and GM-CSF than paired CD8+ T-cell subsets and their equivalents in blood. After 6m and 12m of natalizumab treatment, Th1-like Th17 cells accumulated and showed an increased capacity to co-produce IFN-γ and GM-CSF in RRMS blood. A distinct Th1-like Th17 subpopulation called Th17.1 revealed the highest very late antigen (VLA)-4 expression of all pro-inflammatory Th subsets analyzed in pre-treatment blood, and was the only subpopulation that accumulated in post-treatment blood
(p< 0.001). This was found in RRMS patients who remained free of relapses, but not in patients who encountered relapses during treatment. These data demonstrate that Th1-like and not classical Th17 subsets are important contributors to clinical disease activity and provide a rationale for more targeted and earlier use of T cell-directed treatment in MS.
Disclosure:
Jamie van Langelaar: nothing to disclose
Roos M. van der Vuurst de Vries: nothing to disclose
Malou Janssen: nothing to disclose
Annet F. Wierenga-Wolf: nothing to disclose
Isis M. Spilt: nothing to disclose
Theodora A. Siepman: nothing to disclose
Georges M. Verjans: nothing to disclose
Erik Lubberts: nothing to disclose
Rogier Q. Hintzen: nothing to disclose
Marvin M. van Luijn: nothing to disclose
Abstract: P997
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Interleukin (IL)-17-producing CD4+ T helper (Th)17 cells are considered key mediators of early MS activity. However, depending on the species and inflammatory milieu, Th17 populations are highly polyfunctional, as reflected by their (co-)production of interferon-gamma (IFN-γ) and granulocyte macrophage colony-stimulating factor (GM-CSF). We performed cross-sectional and longitudinal analyses to refine Th17 effector function in different clinical subgroups of MS. Blood and/or CSF samples were assessed from 60 treatment-naive relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS) patients, and from 17 natalizumab-treated RRMS patients (pre- and both 6m and 12m post-treatment). CIS patients either obtained a second clinical attack within 1 year (CIS-CDMS; n=16) or did not experience subsequent attacks for more than 5 years of follow-up (CIS-CIS; n=16). IFN-γ- and GM-CSF-producing (Th1-like) and not IL-17-producing (classical) Th17 effector memory cells in blood were significantly reduced in CIS-CDMS compared to CIS-CIS (p< 0.01) and healthy control (p< 0.01) groups, as determined by 15-parameter flow cytometry. Similar reductions were found in RRMS blood (p< 0.0001). In the CSF of CIS and RRMS patients, Th1-like Th17 effector memory cells were more abundant and produced higher levels of IFN-γ and GM-CSF than paired CD8+ T-cell subsets and their equivalents in blood. After 6m and 12m of natalizumab treatment, Th1-like Th17 cells accumulated and showed an increased capacity to co-produce IFN-γ and GM-CSF in RRMS blood. A distinct Th1-like Th17 subpopulation called Th17.1 revealed the highest very late antigen (VLA)-4 expression of all pro-inflammatory Th subsets analyzed in pre-treatment blood, and was the only subpopulation that accumulated in post-treatment blood
(p< 0.001). This was found in RRMS patients who remained free of relapses, but not in patients who encountered relapses during treatment. These data demonstrate that Th1-like and not classical Th17 subsets are important contributors to clinical disease activity and provide a rationale for more targeted and earlier use of T cell-directed treatment in MS.
Disclosure:
Jamie van Langelaar: nothing to disclose
Roos M. van der Vuurst de Vries: nothing to disclose
Malou Janssen: nothing to disclose
Annet F. Wierenga-Wolf: nothing to disclose
Isis M. Spilt: nothing to disclose
Theodora A. Siepman: nothing to disclose
Georges M. Verjans: nothing to disclose
Erik Lubberts: nothing to disclose
Rogier Q. Hintzen: nothing to disclose
Marvin M. van Luijn: nothing to disclose