Altered Toll-Like Receptor 9 Responses in Circulating B Cells at the Onset of Extensive Chronic Graft-versus-Host Disease

Abstract

B cells appear to play a role in chronic graft-versus-host disease (cGVHD) as shown in murine models and the success of anti-CD20 B cell antibody treatment in humans. Recent studies have shown that immunostimulatory microbial CpG-DNA splenic responses were enhanced in murine GVHD. We hypothesized that CpG-induced B cell responses are increased in human cGVHD. Newly diagnosed cGVHD patients enrolled on the COG protocol ASCT0031 were divided into early (3-8 months postblood and marrow transplant [BMT]) and late (> or =9 months post-BMT) onset groups and compared to time-matched control BMT patients. A significantly greater percentage of phosphorothioate (PS)-modified CpG stimulated B cells from cGVHD patients demonstrated an increased expression of CD86 compared to controls (P = .0004). This response had a significant correlation between B cell TLR9 expression (r(2) = 0.65; P = .002) and CD86 upregulation using the entirely TLR9-dependent native phosphodiester CpG (P = .003). The PS-modified CpG response at 2 months after initiation of cGVHD therapy demonstrated a trend toward predicting therapeutic response at 9 months post-BMT (P = .07). These findings suggest that an increased number of B cells, primed for a TLR9 response, may play a role in the pathophysiology of cGVHD.

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…5,[39][40][41][42][43][44] Costimulation of T cells via CD86 expressed by APCs delivers a strong costimulatory signal to cognate T cells and has been shown to be critical for development of cGVHD. [45][46][47] In light of our in vivo and in vitro data on costimulatory molecules and given previous reports that IL-4 rapidly induces XBP-1 gene expression through STAT6 signaling, 5 we propose that XBP-1 promotes the expression of costimulatory molecules CD86, MHCII, and ICOS-L via IL-4/STAT6-dependent signaling through IL-4. 48 Although it is known that IL-4/STAT6 signaling regulates transcription of CD86 and MHCII genes in response to IL-4, 49-51 the role of XBP-1 in this B-cell process has not been clearly established.…”

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease–associated dysgammaglobulinemia

“…11,14,15,[24][25][26][27] We recently observed a significant distortion of B-cell homeostasis seen in significant elevation of CD19 ϩ CD21 low immature B cells and deficiency of CD19 ϩ CD27 ϩ memory B cells in patients with active cGVHD. 14 Because other hallmarks of affection of the patients' immune system by cGVHD are hypogammaglobulinemia 20,28,29 and functional hyposplenism, which can occur in up to 15% of HCT patients 21,30 on the one hand and hypergammaglobulinemia 31,32 and presence of autoantibodies at onset and related to activity of cGVHD on the other hand, 20,33,34 we analyzed different cGVHD patient cohorts defined by serum Ig levels as surrogate markers for B-cell function.…”

Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus-host disease

“…14 B cells were also recently recognized to be an important part of the immune response in chronic GVHD. 6,15,16,19,20 The Boston group described that patients with chronic GVHD had increased plasma levels of B-cell activation factor of the TNF family (BAFF). 18,28 Thus, T cells and B cells play major roles in the pathogenesis of chronic GVHD.…”

“…[10][11][12][13][14] While donor T cells are known to play a major role, B cells are also important. [15][16][17][18][19] A positive response to treatment with rituximab was reported in 50-70% of patients who failed to respond to first-line treatment with glucocorticoids and calcineurin inhibitors. 20 Extracorporeal photopheresis has been used with variable efficacy to treat chronic GVHD.…”