Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

Flynn, Ryan; Du, Jing; Veenstra, Rachelle G.; Reichenbach, Dawn K.; Panoskaltsis‐Mortari, Angela; Taylor, Patricia A.; Freeman, Gordon J.; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Sarantopoulos, Stefanie; Luznik, Leo; Maillard, Ivan; Koreth, John; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jérôme; Dubovsky, Jason A.; Byrd, John C.; MacDonald, Kelli P. A.; Hill, Geoffrey R.; Blazar, Bruce R.

doi:10.1182/blood-2014-03-562231

Cited by 186 publications

(242 citation statements)

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“…[47][48][49][50] Elevated levels of IL-21 51 and IL-21-producing cells 52 have been found in human cGVHD and a deleterious role of IL-21 has been demonstrated in mouse models of cGVHD. 25,52 Accordingly, we found relatively high basal levels of phosphorylated STAT3 as well as increased circulating plasmablasts in cGVHD patients in our study.Breg frequencies were increased after ECP treatment in 5 patients. ECP possibly induces Tregs through incompletely elucidated For personal use only.…”

mentioning

confidence: 52%

“…GC reactions are hardly accessible for studies in humans, but have indeed been shown to play a role in mouse models of cGVHD. 25,26 Further mechanistic studies will define the accurate role of the different B cells subsets in regulating the alloimmune response.…”

Section: Discussionmentioning

confidence: 99%

“…21,24 GC reactions may play a major role in the pathogenesis of cGVHD in mice. [25][26][27] GC-derived "plasmablast-like" B cells are increased in human cGVHD. 11 Recent studies have shown that the latter cell subset bears regulatory properties and may be the main IL-10-producing B-cell subset in mice.…”

Section: Introductionmentioning

confidence: 99%

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CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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confidence: 52%

Section: Discussionmentioning

confidence: 99%

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CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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“…We demonstrated recently that, consistent with this, systemic IL-17 levels increase late after clinical BMT, at a time when cGVHD develops (45). It is also clear that T follicular helper (T FH ) cells and IL-21 play important roles in the development of cGVHD via the stimulation of germinal center B cells and alloantibody generation (46). This is particularly relevant to bronchiolitis obliterans, because preliminary evidence suggests that Th17 differentiation and CSF1 dysregulation are also involved in this aberrant immunological pathway (44).…”

Section: Cytokines and Cgvhdmentioning

confidence: 64%

Cytokines in Graft-versus-Host Disease

Henden

Hill

2015

The Journal of Immunology

153

117

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Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine.

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“…Homozygosity at the MHC in inbred mice allows for controlled analysis of the effect of the degree of major and minor antigen mismatch between donor and recipient on the outcome of GVHD severity and target organ pathogenesis. Depending on the donor and recipient mice strains and the degree of disparity at the MHC, major and minor mismatch may result in either acute [21,22] or chronic GVHD [23,24]. Further, the type of GVHD that manifests may be either CD4+ or CD8+ T cellmediated, depending on the murine model used and the differential reconstitution of T-cell subsets after HSCT.…”

Section: Differences In Agvhd Responses Between Speciesmentioning

confidence: 99%

Preclinical modeling of hematopoietic stem cell transplantation – advantages and limitations

2015

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Hematopoietic stem cell transplantation, which was first successfully performed in the 1950s, remains a critical therapeutic modality for treatment of a diverse array of diseases, including a multitude of hematological malignancies, autoimmune disorders, amyloidosis and inherited genetic hematological disorders. Although great advances have been made in understanding and application of this therapy, significant complications still exist, warranting further investigation. Of critical importance, graft‐versus‐host disease (GVHD), in both acute and chronic forms, remains a major complication of hematopoietic stem cell transplantation, responsible for both the development of chronic illness and morbidity, as well as mortality. Use of an appropriate preclinical model may provide significant insight into the mechanistic pathways leading to the development and progression of graft‐versus‐host disease, as well as cancer in general. However, existing preclinical modeling systems exhibit significant limitations, and development of models that recapitulate the complex and comprehensive clinical scenario and provide a tool by which therapeutic intervention may be developed and assessed is of utmost importance. Here, we review the present status of the field of graft‐versus‐host disease research. We discuss and summarize the preclinical models currently in use, as well as their advantages and limitations.

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Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

Cited by 186 publications

References 35 publications

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Cytokines in Graft-versus-Host Disease

Preclinical modeling of hematopoietic stem cell transplantation – advantages and limitations

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