Engineering chimeric autoantibody receptor T cells for targeted B cell depletion in multiple sclerosis model: An in-vitro study

Maryam Sahlolbei; Mohammadreza Azangou-Khyavy; Javad Khanali; Babak Khorsand; Aref Shiralipour; Naser Ahmadbeigi; Zahra Madjd; Hossein Ghanbarian; Alireza Ardjmand; Seyed Mahmoud Hashemi; Jafar Kiani

doi:10.1016/j.heliyon.2023.e19763

Engineering chimeric autoantibody receptor T cells for targeted B cell depletion in multiple sclerosis model: An in-vitro study

Heliyon. 2023 Sep 1;9(9):e19763. doi: 10.1016/j.heliyon.2023.e19763. eCollection 2023 Sep.

Authors

Maryam Sahlolbei^{1

2}, Mohammadreza Azangou-Khyavy³, Javad Khanali³, Babak Khorsand^{4

5}, Aref Shiralipour⁶, Naser Ahmadbeigi⁷, Zahra Madjd², Hossein Ghanbarian⁶, Alireza Ardjmand⁸, Seyed Mahmoud Hashemi^{9

10}, Jafar Kiani^{1

2}

Affiliations

¹ Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
² Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
³ School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴ Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁵ Computer Engineering Department, Faculty of Engineering, Ferdowsi University of Mashhad, Mashhad, Iran.
⁶ Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁷ Gene Therapy Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
⁸ NSW Health Pathology, Sydney, New South Wales, Australia.
⁹ Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁰ Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

Background: Recent evidence suggests that B cells and autoantibodies have a substantial role in the pathogenesis of Multiple sclerosis. T cells could be engineered to express chimeric autoantibody receptors (CAARs), which have an epitope of autoantigens in their extracellular domain acting as bait for trapping autoreactive B cells. This study aims to assess the function of designed CAAR T cells against B cell clones reactive to the myelin basic protein (MBP) autoantigen.

Methods: T cells were transduced to express a CAAR consisting of MBP as the extracellular domain. experimental autoimmune encephalomyelitis (EAE) was induced by injecting MBP into mice. The cytotoxicity, proliferation, and cytokine production of the MBP-CAAR T cells were investigated in co-culture with B cells.

Results: MBP-CAAR T cells showed higher cytotoxic activity against autoreactive B cells in all effector-to-target ratios compared to Mock T cell (empty vector-transduced T cell) and Un-T cells (un-transduced T cell). In co-cultures containing CAAR T cells, there was more proliferation and inflammatory cytokine release as compared to Un-T and Mock T cell groups.

Conclusion: Based on these findings, CAAR T cells are promising for curing or modulating autoimmunity and can be served as a new approach for clone-specific B cell depletion therapy in multiple sclerosis.

Keywords: Autoreactive B cells; Chimeric autoantibody receptor (CAAR); Experimental autoimmune encephalomyelitis (EAE); Multiple sclerosis (MS); Myelin basic protein (MBP).