The Role of B Cell Targeting in Chronic Graft-Versus-Host Disease

Abstract

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously felt to be a T cell disease has more recently been shown to involve activation of both T and B cells, as well as a number of cytokines. With a better understanding of its pathophysiology have come more expansive preclinical and clinical trials, many focused on B cell signaling. This report briefly reviews our current understanding of cGVHD pathophysiology and reviews clinical and preclinical trials with B cell-targeted agents.

Neuronal surface antibody-mediated encephalopathy as manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…Previous clinical reports mainly mentioned T-cell mediated CNS lesions or encephalitis (Iwasaki et al, 1993;Kamble et al, 2007;Marosi et al, 1990;Saad et al, 2009). However, it is now recognized that B cells play an important role in the pathophysiology of systemic chronic GVHD (MacDonald et al, 2017;Rhoades and Gaballa, 2017). Considering biological signs of B-cell activation in our patient, we added anti-B cell treatment with rituximab (an anti-CD20 antibody) to corticosteroid-cyclophosphamide combination therapy.…”

Ibrutinib for Chronic Graft-Versus-Host Disease

“…1,2,4,5 GvHD is often a serious condition that causes significant morbidity; it is a prognostic indicator of poor outcomes and is 1 of the leading causes of mortality in patients following stem cell transplant. 2,4,6 A risk factor for developing GvHD is receipt of a graft from an unrelated or unmatched donor. 4 Symptoms of GvHD often manifest initially as mouth sores and/or skin rash, 4 and can progress to include dry mouth, gastrointestinal distress, elevated serum bilirubin, fatigue, shortness of breath and/or trouble breathing, and musculoskeletal pain and weakness.…”

“…8 This and other challenges in diagnosing and treating CGvHD are exacerbated by current limitations in understanding of both conditions because of insufficient data from small and/or methodologically limited studies as well as a lack of standardized thresholds and definitions. 6,16 For instance, although CGvHD was originally thought to be a disease primarily of the T cells, recent research suggests that both T cells and B cells are involved, 15 This finding catalyzed further studies investigating the role of treatments targeting B cells. 6,16 Treatments for CGvHD target the reduction of symptoms while aiming to mitigate side effects and adverse events caused by therapy.…”

Update on ocular graft-versus-host disease

“…[ 97 98 ] While cGVHD was conventionally thought to be T-helper cell2-mediated, recent evidence points towards the role of T-helper17 cells as key effector cells in cGVHD which is supported by raised tear levels of IL-6, IL-17 A, IL-1b, and TNF-α in oGVHD patients. [ 99 102 ] IL-17A and IL-6 may also have a role in triggering proliferation and alterations of the germinal B-cell, which are now believed to influence cGVHD pathogenesis. [ 103 ]…”

“…[ 9 ] An extensive tear proteomic profiling identified 79 proteins to be differentially expressed in oGVHD as compared to non-oGVHD. [ 102 ] Structural proteins, nucleic acid binders, and oxidoreductase enzymes were seen to be prominently upregulated proteins while enzyme modulators, hydrolases, carrier proteins, receptor binding proteins, and defense and immunity-related proteins were down-regulated. Histone proteins, which are known to have pro-inflammatory proteins, were the most highly unregulated and may be associated with the increased NET formation in these eyes while Lipocalin-1, which has numerous protective effects, was the most downregulated protein.…”