Electronic Poster | Session 2

083 – Anti-CD20 therapy has limited impact on CD11c+ B cells, though overall improves the balance of inflammatory and regulatory B cells in patients with multiple sclerosis

Koji Shinoda (1, 2) – Ayman Rezk (1, 2) – Rui Li (1, 2) – Amit Bar-Or (1, 2 3)
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, PA, USA (1) – Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, PA, USA (2) – Children’s Hospital of Philadelphia, University of Pennsylvania, PA, USA (3)

Anti-CD20 therapy targets a broad range of B cells and a small subset of T cells, and has emerged as a high efficacy treatment for patients with multiple sclerosis (MS). Circulating B cells in untreated patients with MS exhibit an abnormal balance of pro-inflammatory and regulatory cytokine-producing B cell subpopulations. While anti-CD20 therapy has been thought to deplete both these subpopulations from the circulation relatively indiscriminately, differential impact of the depletion phase on smaller yet potentially relevant subsets has not been examined. In addition, relatively little is known about the profiles and kinetics of B-cell subset reconstitution, even after short anti-CD20 exposure. Here, we aimed to clarify the phenotypic and functional changes in circulating B cells following treatment initiation with the humanized anti-CD20 ocrelizumab, by comparing serial (baseline, 3-month and 6-month) profiles using deep immunophenotyping and flow cytometry of peripheral blood mononuclear cells in treatment-naive MS patients. B cells were largely but not completely depleted, 3 months after treatment initiation. Specifically, we found that CD11c+ B cells (implicated as pro-inflammatory in other systemic autoimmune diseases) in addition to plasmablasts, were less efficiently depleted. By the time of the 6-month infusion, B cells were partially repopulated, though to differing degrees across individuals. In general, CD10+ transitional B cells (implicated as anti-inflammatory), as well as a subset of memory B cells, preferentially repopulated by 6 months. The repopulating B cells exhibited decreased levels of surface activation markers, and increased levels of surface regulatory markers. The ratios of IL-6/IL-10-producing B cells (previously implicated in driving pro-inflammatory Th17 T cell responses) were significantly diminished at month 6 compared to the treatment-naïve baseline. Our data unexpectedly demonstrates diminished susceptibility of the CD11c+ B cell subset to anti-CD20 therapy. The kinetics of B cell reconstitution exhibit a degree of heterogeneity across MS patients, with an overall improved inflammatory/regulatory balance, even after an initial cycle of anti-CD20 therapy.