Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis

Akgün, Katja; Blankenburg, Judith; Marggraf, Michaela; Haase, Rocco; Ziemssen, Tjalf

doi:10.3389/fimmu.2020.00056

Cited by 21 publications

(22 citation statements)

References 39 publications

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“…PBMCs were isolated and processed according to standard operating procedures (SOPs) as described before 13 . In short, PBMCs were isolated from heparinized or citrated blood and cryo‐preserved at −130°C.…”

Section: Methodsmentioning

confidence: 99%

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Moser

Schwenker

Seiberl

et al. 2020

Ann Clin Transl Neurol

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Objectives: To expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short-term effects on peripheral immune cell subsets. Methods: In this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD. The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry. Results: We found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper-repopulation of maturing B cells. Counts of classical (À65%) and various nonclassical TH17 cells (À84% to À87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of classswitched memory B-cell phenotypes (À87% to À95%). The nadir of TH cells was more pronounced in the second treatment year. We observed a proportional surge of CD20 T-cell subsets and an expansion of regulatory T, B and NK cells. Natural killer T cells (NKT) were only depleted in year two and did not recover. Interpretation: Peripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD. While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course. Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease-modifying effect of CLAD.

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Section: Methodsmentioning

confidence: 99%

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Moser

Schwenker

Seiberl

et al. 2020

Ann Clin Transl Neurol

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“…Alemtuzumab treatment cycles are generally given at least 12 months apart, but this interval may be extended up to 18 months, which supports the important activity of memory B cells as they, and CD4 T cells, can be depleted for at least this time (Tuohy et al, 2015, Havrdova et al, 2017, Akgün et al, 2020. However, alemtuzumab induces transient monocyte depletion and can induce very long-term CD4 and CD8 T cell depletion (Kousin-Ezewu et al, 2014;Thomas et al, 2016, Baker et al, 2017bAkgün et al, 2020). This influences responses to viral and other infections (Cohen et al, 2012;Wray et al, 2019) and could thus impact on SARS-CoV-2 outcome.…”

Section: Alemtuzumabmentioning

confidence: 98%

“…This is a CD52-depleting antibody that induces long-lasting and marked (80-90%) depletion of CD4, CD8 T cells and memory B cells (Table 2. Baker et al 2017;Akgün et al, 2020). Alemtuzumab induces long-term disease remission if treated sufficiently early after symptom onset (Cohen et al, 2012.…”

Section: Alemtuzumabmentioning

confidence: 99%

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Baker

Amor

Kang

et al. 2020

Multiple Sclerosis and Related Disorders

103

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Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. Observations: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic. 1. SARS-Cov-2 and COVID-19 a new pandemic COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) infection (Zhu et al., 2020a; Zhou et al., 2020). About 80% of people infected with SARS-CoV-2 develop a self-limiting illness, 20% require hospitalisation, largely due to cardiovascular issues and about 5% require critical care and potential ventilatory support (Kimball et al., 2020; Day. 2020). The mortality in those requiring ventilatory support is about 40-50% (Weiss and Murdoch 2020; Zhu et al., 2020b). Death from COVID-19 is associated with older age and comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al., 2020a; Lippi et al., 2020; Richardson et al., 2020). Mortality in young people and those without comorbidities may be related to excessive viral load (Lui et al 2020a; Chen et al., 2020a). Whilst the typical clinical features requiring self-isolation, and potentially hospitalization are fever, dry cough and shortness of breath related to respiratory tract infection, other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al., 2020b; Richardson et al., 2020; Huang et al., 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develo...

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“…If COVID‐19‐related vaccine responses become a key concern among people with MS or other autoimmune diseases choosing treatment options, the selection of B cell‐depleting agents that allow quick repopulation of B cells may be relevant for optimum vaccine readiness. Continuous B cell depletion with ocrelizumab and rituximab will clearly limit naive B cell repopulation; however, memory B cell depletion persists for a significant time after depletion with rituximab and alemtuzumab, consistent with the slow repopulation of this subset [99,100,102,103]. This suggests a possibility for extended interval dosing or dosing interruption to allow immature B cells to recover to facilitate vaccination, while maintaining low levels of pathogenic memory B cells.…”

Section: Introductionmentioning

confidence: 99%

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Baker

Roberts

Pryce

et al. 2020

Clinical and Experimental Immunology

168

196

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Based on the known and emerging biology of autoimmune diseases and COVID‐19, it was hypothesised that whilst B‐cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, it may inhibit or blunt the protective immunity following infection and vaccination. This is supported clinically, as the majority of SARS‐CoV‐2 infected, CD20‐depleted people with autoimmunity, have recovered. However, in CD‐20 treated people until naïve B‐cells repopulate, based on B‐cell repopulation‐kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose‐interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.

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Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis

Cited by 21 publications

References 39 publications

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

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