Immunoregulatory effects of RGMb in gut inflammation

Abstract

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT). Current strategies to prevent GvHD with immunosuppressive drugs carry significant morbidity and may affect the graft-versus-tumor (GVT) effect. Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Current strategies to prevent colitis with immunosuppressive drugs carry significant morbidity. Recently, Repulsive Guidance Molecule b (RGMb) has been identified as part of a signaling hub with neogenin and BMP receptors in mice and humans. In addition, RGMb binds BMP-2/4 in mice and humans as well as PD-L2 in mice. RGMb is expressed in the gut epithelium and by antigen presenting cells, and we found significantly increased expression in mouse small intestine after total body irradiation HCT conditioning. We hypothesized that RGMb may play a role in GvHD and IBD pathogenesis by contributing to mucosal inflammation. Using major-mismatched HCT mouse models, treatment with an anti-RGMb monoclonal antibody (mAb) that blocks the interaction with BMP-2/4 and neogenin prevented GvHD and improved survival compared to isotype control (75% versus 30% survival at 60 days after transplantation). The GVT effect was retained in tumor models. Using an inflammatory bowel disease dextran sulfate sodium model, treatment with anti-RGMb blocking monoclonal antibody but not isotype control prevented colitis and improved survival compared to control (73% versus 33% at 21 days after treatment) restoring gut homeostasis. Anti-RGMb mAb (9D1) treatment decreased IFN-γ and significantly increased IL-5 and IL-10 in the gut of the treated mice compared to the isotype control treated mice.

Research Progress on RGMb and its Signaling Pathway

“…The BMP pathway mentioned above is also related to it. PD-L2 and BMP can simultaneously bind to RGMb at different binding sites to form a more complex trimeric complex [31,32]. RGMb is also a binding ligand of PD-L2, found by recent studies.…”

The role of PD-1 signaling in health and immune-related diseases

“…PD-L2 expression in human tumor samples generally correlates with that of PD-L1; however, PD-L2 expression was also present in the absence of PD-L1 in subsets of patient samples ( 39 ). Additionally, the role of PD-L2 is highlighted in studies of allergy and tolerance, and the second binding partner of PD­L2, repulsive guidance molecule b (RGMb), was discovered ( 31 , 40 , 41 ). RGMb is a glycosylphosphatidylinositol (GPI)-anchored protein and is one of three members of the repulsive guidance molecule family (RGMa/b/c) ( 31 ).…”

“…RGMb is a glycosylphosphatidylinositol (GPI)-anchored protein and is one of three members of the repulsive guidance molecule family (RGMa/b/c) ( 31 ). RGMb also serves as a co-receptor for bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and neogenin, resulting in a supercomplex of BMP-BMPR-RGMb-neogenin in cis, and PD-L2 may bind in trans with the RGMb supercomplex to regulate downstream pathways ( 31 , 40 , 42 ) ( Figure 3 ). The functional role of PD-L2 in this supercomplex requires further study.…”

Targeting programmed death ligand 2/repulsive guidance molecule b pathway: a novel strategy to subdue tumor immunotherapy resistance to anti‐programmed death 1/programmed death ligand 1

“…Although previous studies have demonstrated that gut microbiome can modulate local immune environment directly or indirectly through their metabolites, such as acetate, short‐chain fatty acids, and butyrate, 2 there are some detailed mechanisms remain unknown, such as which effector molecular from C. cateniformis and how it regulates immune cells (DCs and T cells) function by affecting endogenous expression of PD‐L2/RGMb from gut to dLNs and tumor microenvironment (Figure 1). It's worth noting that as one of the four members of the RGM family, RGMb, originally identified as a crucial molecular in nervous system development, is ubiquitously expressed in a variety of tissues and immune cells, and binds to multiple proteins such as bone morphogenetic proteins 2 and 4, cytotoxic T‐lymphocyte associated protein 4, and neogenin to participate in multiple processes including the regulation of inflammatory factor expression, infiltration of T cells 3 . Therefore, blocking RGMb may result in some side effects like increasing the risk of acute kidney injury 4 .…”

“…It's worth noting that as one of the four members of the RGM family, RGMb, originally identified as a crucial molecular in nervous system development, is ubiquitously expressed in a variety of tissues and immune cells, and binds to multiple proteins such as bone morphogenetic proteins 2 and 4, cytotoxic T‐lymphocyte associated protein 4, and neogenin to participate in multiple processes including the regulation of inflammatory factor expression, infiltration of T cells. 3 Therefore, blocking RGMb may result in some side effects like increasing the risk of acute kidney injury. 4 Collectively, this work provides new insight for understanding microbiome‐related immunotherapy resistance and offers innovative tactics to subdue the resistance of anti‐tumor immune therapy, which may benefit cancer patients who do not respond to anti‐PD‐1/PD‐L1 therapy.…”