Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

Abstract

Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1b and TNF-a levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

Repulsive Guidance Molecule-a and Central Nervous System Diseases

“…RGMa in dendritic cells can also bind to Neogenin on CD4 + T cells to activate inflammatory cells, enhance the adhesion between inflammatory cells and ICAM-1, and indirectly regulate the release and diffusion of cytokines [ 31 ]. Treatment with RGMa neutralizing antibody can cause dendritic cell tolerance and immunomodulatory function; reduce the levels of MHC II, CD86, CD80, and CD40; decrease the levels of IL-12, IL-1 β , and TNF- α ; and increase the secretion of IL-10, resulting in reducing T cell proliferation and enhancing the T cell differentiation into Th2 cells [ 32 ].…”

Phase 1 Evaluation of Elezanumab (Anti–Repulsive Guidance Molecule A Monoclonal Antibody) in Healthy and Multiple Sclerosis Participants

“…RGMa is a potent modulator of axonal growth, myelination, and downstream immunoregulatory molecules (eg, interlukin-10 [IL -10]) that are important factors for inhibiting neuronal and oligodendroglial regeneration and functional recovery after central nervous system (CNS) trauma or inflammation. [9][10][11][12][13][14] Postmortem evidence from MS patient brain sections showed upregulated RGMa at active and chronic CNS lesions. 15 RGMa neutralization is a novel approach that may provide neurorestoration/regeneration and functional recovery in a variety of degenerative CNS diseases.…”

“…Elezanumab (ABT‐555) is a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa). RGMa is a potent modulator of axonal growth, myelination, and downstream immunoregulatory molecules (eg, interlukin‐10 [IL‐10]) that are important factors for inhibiting neuronal and oligodendroglial regeneration and functional recovery after central nervous system (CNS) trauma or inflammation 9–14 . Postmortem evidence from MS patient brain sections showed upregulated RGMa at active and chronic CNS lesions 15 .…”

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants

“…13 Repulsive guidance molecule A (RGMa) is a potent modulator of axonal growth, myelination, and downstream immunoregulatory molecules, which impact neuronal and oligodendroglial survival as well as regeneration after trauma or inflammation in the central nervous system and can also influence functional recovery. [14][15][16][17][18][19] Increased RGMa expression has been observed in patients following acute stroke 20,21 and SCI upregulates RGMa expression in the injured rodent, nonhuman primate, and human spinal cord. [22][23][24][25] Thus, neutralization of RGMa is a novel approach for treatment of various degenerative central nervous system diseases and conditions.…”