scholarly journals Blockade of osteopontin reduces alloreactive CD8+ T cell–mediated graft-versus-host disease

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1723-1733 ◽  
Author(s):  
Fang Zhao ◽  
Yi Zhang ◽  
Hao Wang ◽  
Min Jin ◽  
Shan He ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.

scholarly journals CCR2 is required for CD8-induced graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3322-3330 ◽  
Author(s):  
Theis H. Terwey ◽  
Theo D. Kim ◽  
Adam A. Kochman ◽  
Vanessa M. Hubbard ◽  
Sydney Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Migration

AbstractGraft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.

scholarly journals Absence of β7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1703-1711 ◽  
Author(s):  
Elisha Waldman ◽  
Sydney X. Lu ◽  
Vanessa M. Hubbard ◽  
Adam A. Kochman ◽  
Jeffrey M. Eng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Morbidity And Mortality ◽  
Cell Infiltration ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Infiltration ◽  
Donor T Cells

The α4β7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the β7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive β7-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of β7-/- donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versus-tumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of β7-/- donor T cells. In conclusion, β7-/- donor T cells caused less GVHD morbidity and mortality than WT donor T cells because of selectively decreased T-cell infiltration of the liver and intestines. Our data suggest that strategies to target the β7 integrin have the clinical potential to alleviate or prevent GVHD while sparing or potentiating GVT activity.

scholarly journals Nrf2 regulates CD4+ T cell–induced acute graft-versus-host disease in mice

Blood ◽  
2018 ◽  
Vol 132 (26) ◽  
pp. 2763-2774 ◽  
Author(s):  
Jennifer J. Tsai ◽  
Enrico Velardi ◽  
Yusuke Shono ◽  
Kimon V. Argyropoulos ◽  
Amanda M. Holland ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Function ◽  
Donor T Cells ◽  
Acute Graft

Abstract Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2−/− donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2−/− donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2−/− donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.

scholarly journals Cytokines and costimulation in acute graft-versus-host disease

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 418-428 ◽  
Author(s):  
Geoffrey R. Hill ◽  
Motoko Koyama
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 12 ◽  
Target Tissue ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Acute Graft

Abstract Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy used prior to alloSCT induces the release of endogenous alarmins (eg, HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (eg, lipopolysaccharide, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen-presenting cells (APCs) to efficiently present alloantigen to donor T cells while releasing cytokines (eg, interleukin-12 [IL-12], IL-23, IL-6, IL-27, IL-10, transforming growth factor-β) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent costimulatory signals at the APC–T-cell interface (eg, CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent coinhibitory signals (eg, CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T-cell function and ensuing secretion of pathogenic cytokines (eg, IL-17, interferon-γ, tissue necrosis factor, granulocyte-macrophage colony-stimulating factor) and cytolytic degranulation pathway effectors (eg, perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T-cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.

T cell receptor excision circle levels in CD94-expressing CD8 T Cells during graft-versus-host disease

2008 ◽  
Vol 49 (7) ◽  
pp. 1306-1310 ◽  
Author(s):  
Junichi Sugita ◽  
Noriaki Iwao ◽  
Junji Tanaka ◽  
Naoko Kato ◽  
Souichi Shiratori ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Host Disease ◽  
Graft Versus Host

scholarly journals Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2476-2484 ◽  
Author(s):  
Hong Zheng ◽  
Catherine Matte-Martone ◽  
Hongmei Li ◽  
Britt E. Anderson ◽  
Srividhya Venketesan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Myelogenous Leukemia ◽  
Effector Memory ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T cells (TEMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4+ TEMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating gene-deficient leukemias and using perforin-deficient T cells, we demonstrate that direct cytolytic function is essential for TEM-mediated GVL, but that GVL is retained when killing via FasL, TNF-α, TRAIL, and perforin is individually impaired. However, TEM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEMs as a clinically applicable cell therapy for promoting GVL and immune reconstitution, particularly in MHC-mismatched haploidentical alloSCTs in which T cell–depleted allografts are commonly used to minimize GVHD.

scholarly journals Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽  
2020 ◽  
Author(s):  
Cheng Yin Yuan ◽  
Vivian Zhou ◽  
Garrett Sauber ◽  
Todd M Stollenwerk ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Cannabinoid Receptor ◽  
Therapeutic Targeting ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

scholarly journals Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease

2019 ◽  
Vol 3 (7) ◽  
pp. 984-994 ◽  
Author(s):  
Jennifer S. Whangbo ◽  
Haesook T. Kim ◽  
Sarah Nikiforow ◽  
John Koreth ◽  
Ana C. Alho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Low Dose ◽  
B Cell Lymphoma ◽  
Host Disease ◽  
Graft Versus Host ◽  
Response Groups

Abstract Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8+ T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor β (TCRβ) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.

Resting B Cells Suppress CD8+ T Cell Function and Prevent the Induction of Graft Versus Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3111-3111
Author(s):  
David S. Ritchie ◽  
Victoria Watt
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
In Vivo Models ◽  
Host Disease ◽  
Graft Versus Host

Abstract B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells, induce T cell anergy via TGF-b production, down regulate IL-12 production by dendritic cells (DC) and influence Th1/Th2 differentiation via the production of regulatory cytokines. Through these mechanisms, B cells can exert a regulatory function in in vivo models of T cell immunity including, experimental autoimmune encephalitis (EAE) and rheumatoid arthritis (RA). Recently, B cells have been shown to be essential in the prevention of effector T cell differentiation in a model of autoimmunity. We have previously shown that resting B cells inhibited tumor protection induced by dendritic cells vaccination. Inhibition of DC immunity by B cells was independent of presentation of major histocompatibility molecule (MHC) class-I bound tumor antigen but dependent on the expression of class-II MHC. Furthermore the inhibitory effect of B cells was lost if the B cells were activated by CD40L or if CD4+/CD25+ regulatory T cells (Treg) were depleted. These studies have been further extended to examine the role of resting B cells on the induction and severity of graft versus host disease (GVHD) induced in a major MHC mismatch model. We have found that mice transplanted with B cell depleted marrow revealed more rapid CD8+ T cell engraftment, higher IL-2 and IFN-γ production, more severe GVHD and shorter survival. Conversely, those who received additional resting B cells at the time of marrow infusion were substantially protected from GVHD. These findings indicate that resting B cells may regulate T cell activation, in part via the suppressive effects of Treg, but also through their important role in T cell homeostasis. Resting B cells may therefore limit the efficacy of DC based immunotherapy or alternatively be used therapeutically to limit CD8+ T cell autoimmunity including GVHD.

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