RT Journal Article
SR Electronic
T1 CAR-T Cell–Mediated B-Cell Depletion in Central Nervous System Autoimmunity
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200080
DO 10.1212/NXI.0000000000200080
VO 10
IS 2
A1 Sasha Gupta
A1 Milos Simic
A1 Sharon A. Sagan
A1 Chanelle Shepherd
A1 Jason Duecker
A1 Raymond A. Sobel
A1 Ravi Dandekar
A1 Gregory F. Wu
A1 Wesley Wu
A1 John E. Pak
A1 Stephen L. Hauser
A1 Wendell Lim
A1 Michael R. Wilson
A1 Scott S. Zamvil
YR 2023
UL http://nn.neurology.org/content/10/2/e200080.abstract
AB 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.BM=bone marrow; CAR=chimeric antigen receptor; Cy=cyclophosphamide; DEG=differentially expressed gene; EAE=experimental autoimmune encephalomyelitis; GFP=green fluorescent protein; IP=intraperitoneal; mAb=monoclonal antibody; MHC=major histocompatibility complex; MOG=myelin oligodendrocyte protein; MSVG=mouse stem cell virus–based splice-gag vector; UCSF=University of California, San Francisco