CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity.

BACKGROUND AND OBJECTIVES: Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS. METHODS: Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation. RESULTS: Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone. DISCUSSION: In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.

Remote Observational Research for Multiple Sclerosis: A Natural Experiment.

BACKGROUND AND OBJECTIVES: Prospective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations. METHODS: Between March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 "matched visits," that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected. RESULTS: The costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint (p < 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority, p < 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS. DISCUSSION: Altogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants.

Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors (AChR) or, in a minority of patients, to muscle specific kinase (MuSK). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two MG subtypes (AChR or MuSK). The antibodies are thought to be T-cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of MG. METHODS: An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors (BCR) in naive populations was applied to specimens collected from patients with either AChR or MuSK MG and healthy controls. Radioimmuno- and cell-based assays were used to measure BCR binding to AChR and MuSK. RESULTS: The frequency of polyreactive and autoreactive BCRs (n = 262) was higher in both AChR and MuSK MG patients than in healthy controls. None of the MG-derived BCRs bound AChR or MuSK. INTERPRETATION: The results indicate that both these MG subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in MG and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells.