Interleukin 21 blockade modulates activated T- and B-cell homeostasis via B-cell activating factor pathway–mediated inhibition in a murine model of acute graft-versus-host disease

Graft-versus-host disease (GVHD) has posed many challenges in allogeneic HSCT. Thanks to the development of immunomodulating approaches, the mortality of acute GVHD (aGVHD) is drastically decreased. Nevertheless, chronic GVHD (cGVHD) is became the leading causes of death in patients who survived of aGVHD. Various studies have demonstrated the essential role of B cells in the development of cGVHD. B cells are directly involved in allogeneic reactions through a variety of mechanisms such as alloantibody production, triggering complement system, promoting antibody-dependent cellular cytotoxicity (ADCC), and cross-presentation of immune complexes. It has been known that the pathways involved in the B-cell homeostasis and survival, such as BAFF, BCR, and Notch2 signaling pathways are abnormal in cGVHD. Post-HSCT lymphopenia triggers the continuous release of BAFF, leading to abnormalities in B cell homeostasis, and increasing the survival of alloreactive/autoreactive B cells, leading to production of allo/auto-antibodies. On the other hand, reduction of regulatory B cells following HSCT, causes loss of T cell peripheral tolerance, leading to cGVHD incidence. Therefore, B cells deserve special consideration in allogeneic HSCT, and targeting alloreactive B cells might be a promising approach in cGVHD management. In this article, we discussed the role of B cells in pathophysiology of cGVHD. Keywords: Chronic graft-versus-host disease, Hematopoietic stem cell transplantation, B cell, BAFF

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Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

Blood ◽

10.1182/blood-2008-09-177840 ◽

2009 ◽

Vol 113 (16) ◽

pp. 3865-3874 ◽

Cited By ~ 204

Author(s):

Stefanie Sarantopoulos ◽

Kristen E. Stevenson ◽

Haesook T. Kim ◽

Corey S. Cutler ◽

Nazmim S. Bhuiya ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Graft Versus Host Disease ◽

High Plasma ◽

Cell Homeostasis ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

B Cell Homeostasis

Abstract Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell–activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre–germinal center (GC) B cells and post-GC “plasmablast-like” cells, suggesting in vivo BAFF dependence of these 2 CD27+ B-cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.

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Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease

Blood ◽

10.1182/blood-2010-10-307819 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2275-2283 ◽

Cited By ~ 83

Author(s):

Stefanie Sarantopoulos ◽

Kristen E. Stevenson ◽

Haesook T. Kim ◽

Whitney S. Washel ◽

Nazmim S. Bhuiya ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Graft Versus Host Disease ◽

Cell Number ◽

Cell Recovery ◽

Cell Homeostasis ◽

Host Disease ◽

Graft Versus Host ◽

Cell Numbers ◽

B Cell Homeostasis

Abstract Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27+ B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD+ B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-RLoCD20Lo cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.

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Erratum to: Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease

Stem Cell Research & Therapy ◽

10.1186/s13287-016-0336-x ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Kyoung-Woon Kim ◽

Su-Jin Moon ◽

Min-Jung Park ◽

Bo-Mi Kim ◽

Eun-Kyung Kim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Graft Versus Host Disease ◽

Murine Model ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

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TNFAIP8 Deficiency Exacerbates Acute Graft Versus Host Disease in a Murine Model of Allogeneic Hematopoietic Cell Transplantation

Transplantation Journal ◽

10.1097/tp.0000000000003013 ◽

2020 ◽

Vol 104 (3) ◽

pp. 500-510

Author(s):

Reena Kumari ◽

Senthilnathan Palaniyandi ◽

Ethan Strattan ◽

Timothy Huang ◽

Katharina Kohler ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Murine Model ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

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Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease to extracorporeal photopheresis

Blood ◽

10.1182/blood-2011-05-354019 ◽

2011 ◽

Vol 118 (24) ◽

pp. 6446-6449 ◽

Cited By ~ 25

Author(s):

Robert Whittle ◽

Peter C. Taylor

Keyword(s):

B Cell ◽

Graft Versus Host Disease ◽

Skin Disease ◽

Therapeutic Option ◽

Extracorporeal Photopheresis ◽

Host Disease ◽

Disease Response ◽

Graft Versus Host ◽

B Cell Activating Factor ◽

Baff Level

Abstract Extracorporeal photopheresis (ECP) is an important therapeutic option in steroid-refractory chronic graft-versus-host disease (cGVHD). Few biomarkers predicting response exist. We measured serum B-cell activating factor (BAFF) in 46 cGVHD patients receiving ECP before and during treatment course. BAFF level at 1 month of ECP predicted 3- and 6-month skin disease response, with BAFF less than 4 ng/mL associated with significant skin improvement and complete resolution in 11 of 20 patients. High BAFF at 1-month ECP associated with a worsening median 6-month skin score and resolution in 1 of 10 patients. BAFF level at 3 months also predicted the likelihood of maintaining skin disease improvement at 6 months. BAFF level was not correlated directly with extracutaneous cGVHD response, although full cutaneous responders exhibited improved extracutaneous organ response rates compared with skin nonresponders (65% vs 35%). This study suggests that early BAFF measurement during ECP for cGVHD represents a potentially useful biomarker in prediction of treatment outcome.

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