Eomesodermin-expressing CD4+ Th cells and association with pregnancy in multiple sclerosis

Background: Pregnancy in patients with multiple sclerosis (MS) is accompanied by a decline of relapse activity with increased risk of relapses 3 months post-partum, for unknown reasons. Eomesodermin + T-helper cells (Eomes + Th cells) are known to mediate neuroinflammation and disease progression in MS and are induced by prolactin-secreting cells. Objectives: Here, investigated immune cell alterations and the pathophysiological role of Eomes + Th cells for disease activity during pregnancy and post-partum in MS. Methods: We enrolled n  = 81 pregnant patients with relapsing-remitting MS (RRMS), n  = 27 post-partum RRMS and n  = 26 female RRMS control patients under the umbrella of the German Multiple Sclerosis and Pregnancy Registry. Clinical data were collected and immune cell alterations were analysed using flow cytometry. Results: While CD3 + CD4 + Th cells were unaffected, CD3 + CD8 + cytotoxic T-cells were elevated post-partum ( p  = 0.02) with reduced B-cell frequencies ( p  = 0.01) compared to non-pregnant RRMS patients. NK cells were elevated during first trimester ( p  = 0.02) compared to the third trimester. Frequencies of Eomes + Th and Eomes + Tc cells did not differ. There was no correlation of prolactin release and expression of Eomes + Th cells. However, Eomes + Th cells correlated with lower frequencies of regulatory T-cells during second ( r  = −0.42; p  < 0.05) and third trimester ( r  = −0.37; p  < 0.05). Moreover, Eomes + Th cells correlated with frequencies of B-cells during third trimester ( r  = 0.54; p  = 0.02). Frequencies of Eomes + Th cells were not associated with the number of relapses before pregnancy, during pregnancy or post-partum. However, Eomes + Th cells strongly correlated with disability post-partum as assessed using the EDSS ( r  = 0.52; p  = 0.009). Discussion: Pregnancy in MS is associated with robust immunological alterations. Eomes + Th cells are capable of inducing immune cell alterations during the course of pregnancy, most evident during the second and third trimester as shown with a correlation of reduced Treg cells and a significant increase of B-cells. Importantly, Eomes + Th cells correlate with disability post-partum. In summary, during late pregnancy in MS an inflammatory, cytotoxic and dysregulated immunological environment is primed gaining function post-delivery. This may be responsible for post-partum disability accumulation

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination

OBJECTIVE: The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. METHODS: We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. RESULTS: We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). INTERPRETATION: In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity

DataSheet_1_Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination.pdf

ObjectiveThe pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.MethodsWe here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.ResultsWe show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).InterpretationIn summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.</p

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination

$\bf Objective:$ The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells $\it via$ anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. $\bf Methods:$ We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. $\bf Results:$ We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain $CD4^{+}$ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). $\bf Interpretation:$ In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity