Antigen‐specific adaptive immune responses in fingolimod‐treated multiple sclerosis patients

Mehling, Matthias; Hilbert, Patricia; Fritz, Stefanie; Durovic, Bojana; Eichin, Dominik; Gasser, Olivier; Kuhle, Jens; Klimkait, Thomas; Lindberg, Raija L. P.; Kappos, Ludwig; Hess, Christoph

doi:10.1002/ana.22352

Cited by 80 publications

(71 citation statements)

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“…T cell responses are not mitigated, but may be enhanced by FTY720 treatment [43]. This is in agreement with a recent human subject study indicating that the influenza vaccine-specific immune response is actually unmitigated in FTY720-treated MS patients, compared with healthy subjects [44].…”

Section: Discussionsupporting

confidence: 79%

FTY720 mediates activation suppression and G0/G1 cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model

Zeng¹,

Wang²,

Zhu

et al. 2012

Inflamm. Res.

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Section: Discussionsupporting

confidence: 79%

FTY720 mediates activation suppression and G0/G1 cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model

Zeng¹,

Wang²,

Zhu

et al. 2012

Inflamm. Res.

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“…Restricted re-entry to the circulation of CCR7 + lymphocyte populations (naive and central memory T cells, B cells) is attributed to FTY720-mediated internalization of S1P1 on lymphocytes (6). Entry of Ag-reactive T cells into the circulation following influenza vaccination appears unimpaired in FTY720-treated MS patients, suggesting that re-entry restriction is not universal (7).…”

mentioning

confidence: 99%

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

Johnson

Evans

Durafourt

et al. 2011

The Journal of Immunology

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FTY720 (fingolimod) treatment of multiple sclerosis (MS) results in lymphopenia due to increased recruitment into and decreased egress from secondary lymphoid organs of CCR7+ lymphocytes. Although absolute numbers of NK lymphocytes were reported as being unaltered in FTY720-treated MS patients (MS-FTY), such analyses did not detect a change in a minor subset. Because expression of CCR7 has been described on CD56bright NK cells, a minority population of NK cells, we investigated the effect of FTY720 treatment on the phenotype and function of human NK cells in the peripheral circulation of MS patients. MS-FTY patients displayed a decreased proportion of peripheral CD56brightCD62L+CCR7+ NK cells compared with untreated MS and healthy donors. In vitro treatment with FTY720-P increased migration of untreated donor NK cells to CXCL12 while reducing the response to CX3CL1 with similar migration responses seen in NK cells from MS-FTY patients. FTY720-P inhibited sphingosine 1-phosphate–directed migration of CD56bright and CD56dim NK cells subsets from untreated healthy donors. IL-12– and IL-15–stimulated NK cells from MS-FTY patients displayed similar capacity to produce IFN-γ, TNF, IL-10, and MIP-1α cytokines/chemokines compared with NK cells from untreated healthy donors and displayed comparable levels of degranulation in response to K562 tumor cells compared with untreated donors. Subset alterations and function of NK cell populations will need to be considered as part of assessing overall immunosurveillance capacity of patients with MS who will receive sustained FTY720 therapy.

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“…As previously published 6,14 , vaccination of healthy individuals induced a significant influenza-specific cellular and humoral immune response, peaking at day 14 post-vaccination in most individuals (Supplementary Fig. S1).…”

mentioning

confidence: 53%

“…Influenza vaccine responses from previously published local vaccination cohorts were analyzed 6,14 . Study participants were recruited at the University Hospital Basel, Switzerland, Table 1.…”

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confidence: 99%

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Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection

Berger

Greiff

Mehling

et al. 2015

Human Vaccines & Immunotherapeutics

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Vaccines dramatically reduce infection-related morbidity and mortality. Determining factors that modulate the host response is key to rational vaccine design and demands unsupervised analysis. To longitudinally resolve influenza-specific humoral immune response dynamics we constructed vaccine response profiles of influenza A- and B-specific IgM and IgG levels from 42 healthy and 31 HIV infected influenza-vaccinated individuals. Pre-vaccination antibody levels and levels at 3 predefined time points after vaccination were included in each profile. We performed hierarchical clustering on these profiles to study the extent to which HIV infection associated immune dysfunction, adaptive immune factors (pre-existing influenza-specific antibodies, T cell responses), an innate immune factor (Mannose Binding Lectin, MBL), demographic characteristics (gender, age), or the vaccine preparation (split vs. virosomal) impacted the immune response to influenza vaccination. Hierarchical clustering associated vaccine preparation and pre-existing IgG levels with the profiles of healthy individuals. In contrast to previous in vitro and animal data, MBL levels had no impact on the adaptive vaccine response. Importantly, while HIV infected subjects with low CD4 T cell counts showed a reduced magnitude of their vaccine response, their response profiles were indistinguishable from those of healthy controls, suggesting quantitative but not qualitative deficits. Unsupervised profile-based analysis ranks factors impacting the vaccine-response by relative importance, with substantial implications for comparing, designing and improving vaccine preparations and strategies. Profile similarity between HIV infected and HIV negative individuals suggests merely quantitative differences in the vaccine response in these individuals, offering a rationale for boosting strategies in the HIV infected population.

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Antigen‐specific adaptive immune responses in fingolimod‐treated multiple sclerosis patients

Cited by 80 publications

References 20 publications

FTY720 mediates activation suppression and G0/G1 cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model

FTY720 mediates activation suppression and G0/G1 cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection

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