scholarly journals Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2088-2095 ◽  
Author(s):  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Kazutoshi Aoyama ◽  
Ken-ichi Matsuoka ◽  
Kennosuke Karube ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Antigen Presenting

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC–T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell–mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation.

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

scholarly journals Microrna-191 Regulates T-Cell Clonal Expansion during Graft-Versus-Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4433-4433
Author(s):  
Chuanfeng Xiong ◽  
Wei Huang ◽  
Xiaoli Nie ◽  
Ying Huang ◽  
Yiqun Jiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Clonal Expansion ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells

Allogeneic hematopoietic cell transplantation is a potentially curative treatment choice for a wide variety of hematological malignancies. However, graft-versus-host disease (GVHD), which is mediated by donor alloreactive T cells, limits the success of this procedure. Previous studies have demonstrated that several microRNAs (miRs) modulate graft-versus-host disease. miR-191 was previously reported to be able to support T cell survival after TCR stimulation. We hypothesize that miR191 regulates T cell response during GVHD. To test this hypothesis, we first studied miR-191 expression in alloreactive T cells. The result demonstrated that miR-191 was up-regulated in donor T cells isolated from murine GVHD recipients, suggesting that miR-191 may play a role in GVHD induction. We further studied the role of miR-191in GVHD using miR-191 deficient T cells (KO). Lethally irradiated (8.5 Gy) BALB/c mice were injected intravenously with 1×107 T cell-depleted bone marrow (TCDBM) cells along with 1×106 purified T cells from wild-type (WT) or KO mice, which are in C57BL/6 background. Interestingly, all recipients in the WT group died within 35 days after transplantation, while only one out of ten animals died in the KO group during an observation period of 56 days. Body weights and clinical scores were also improved in KO T cell recipients when compared with the WT controls. Similar results were also observed in a second GVHD model (C57BL/6→C3H/HeJ). To understand the mechanism by which miR-191 KO T cells have decreased ability to mediate GVHD, we first measured the ability of KO T cells to respond to alloantigens in vitro in a mixed lymphocytes reaction assay. Dramatically decreased alloresponse was observed with KO T cells as compared with WT T cells. Similarly, decreased clonal expansion was observed in KO T cells in vivo upon challenge with alloantigens as measured by bioluminescent imaging (Figure 1A). These results were further supported by data from a co-transfer experiment, in which equal numbers of WT and KO T cells were transplanted into the same GVHD recipient. At day7 after transplantation, KO T cells showed significantly reduced expansion in the spleen and liver compared with WT T cells. Reduced alloresponses mediated by KO T cells may not due to decreased proliferative capability directly as an in vivo carboxyfluorescein succinimidyl ester (CFSE) assay showed a comparable cell division between WT and KO T cells upon challenge with alloantigens. Rather, increased cell death is responsible for decreased alloresponse observed in KO T cells because dramatically increased number of dead cells was observed in KO group compared with WT group upon response to alloantigens in vitro and vivo. To determine the genes that are regulated by miR-191, we did a screening based on the prediction. Humans and mice share more than 100 predicted targets for miR-191. We chose top 20 of these targets for RT-qPCR screening. The result demonstrated that Taf5 was a target gene of miR-191. Expression of TAF5 protein was down-regulated in activated KO T cells when compared with the WT T cells. Finally, we investigated whether miR-191 KO T cells preserve graft-versus-leukemia effects. 1×106 T cells from WT or KO mice were transplanted into lethally irradiated BALB/c mice along with 1×107 TCDBM cells and 1×105 host-type BCL-1 cells. While all recipients that received only TCDBM and tumor cells developed lethal leukemia/lymphoma, none of WT and KO T cells recipients developed tumor. In conclusion, our findings reveal a critical role of miR-191 during GVHD process and demonstrate that miR-191 is a novel therapeutic target for GVHD. Figure 1 Disclosures No relevant conflicts of interest to declare.

Immunomodulatory Effects of Vitamin D: Implications for the Prevention and Treatment of Graft Versus Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1251-1251
Author(s):  
Jacalyn Rosenblatt ◽  
Adam Bissonnette ◽  
Zekui Wu ◽  
Baldev Vasir ◽  
Corrine Zarwan ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Tritiated Thymidine ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Antigen Presenting

Abstract Allogeneic bone marrow transplantation is a uniquely curative therapy for a subset of patients with hematologic malignancies. However, morbidity and mortality related to graft versus host disease remain substantial. Dendritic cells (DCs) are highly potent antigen presenting cells that play a crucial role in maintaining the balance of immune activation and tolerance as well as the nature of immune reconstitution post-transplant. Persistence of host DCs in the early post transplant period has been shown to play an important role in the activation and expansion of alloreactive lymphocytes and the concomitant risk of GVHD. A major focus of research to enhance outcomes following allogeneic transplantation involves the manipulation of DC recovery post-transplant to minimize activation of alloreactive lymphocytes while preserving anti-tumor immunity responsible for the graft versus disease effect. Vitamin D is a hormone involved in bone metabolism and calcium homeostasis. More recently, vitamin D has been shown to have potent immunomodulatory effects. We have evaluated the effect of vitamin D on the phenotypic and functional characteristics of DC and T cell populations. We have demonstrated that vitamin D hinders the maturation of DCs such that cells that are differentiated in its presence exhibit decreased expression of costimulatory molecules. Peripheral blood mononuclear cells (PBMCs) were isolated from leukopaks obtained from normal donors by ficoll density centrifugation. DCs were generated by culturing the monocyte enriched adherent fraction with GM-CSF (1000 U/ml) and IL-4 (1000 U/ml) for 5 days, followed by maturation in the presence of TNFa (25 ng/ml) for 48 hours. DCs were generated in the presence and absence of 10nM of 1,25 hydroxyvitamin D. Mean expression of the costimulatory molecule CD80 and the maturation marker CD83 decreased from 60% to 37% and 53% to 27% respectively in the presence of vitamin D (N=3). To assess the effect of vitamin D on the functional potency of DCs as antigen presenting cells, the capacity of mature DCs to stimulate allogeneic T cell proliferation in the presence of vitamin D was determined. Mature DCs were generated from peripheral blood precursors and then cultured with allogeneic T cells isolated by T cell separation column at a ratio of 1:10. After 5 days, cocultures were pulsed with tritiated thymidine overnight and proliferation was determined by measuring the stimulation index (SI) as defined by uptake of tritiated thymidine of cocultured cells/uptake of tritiated thymidine of T cells alone. Results of 10 serial studies demonstrated the addition of vitamin D resulted in a blunted T cell proliferative response, with mean SI that decreased from 13 to 5. Similarly, the addition of vitamin D to a coculture of DCs and autologous T cells resulted in a 50% reduction in the T cell proliferative response to tetanus toxoid, a recall antigen. In addition, T cells stimulated by allogeneic DCs in the presence of vitamin D were polarized to secrete Th2 cytokines. In three experiments, the mean percentage of T cells secreting IL-10 increased from 2.7% to 4.4%, while expression of IFNγ decreased from a mean of 2.6% to 1.9% in the presence of vitamin D. The presence of vitamin D did not induce FOXP3 expressing regulatory T cell populations, which accounted for 8% and 7% of the T cell population following stimulation by allogeneic DCs in the presence and absence of vitamin D respectively. These data suggest that exposure to vitamin D exerts a tolerizing influence on T cells mediated by its impact on antigen presenting cells. Vitamin D may therefore have a role in the prevention and treatment of graft versus host disease. A clinical trial evaluating the use of vitamin D in the early post-transplant period for the prevention of GVHD is planned.

scholarly journals Dendritic cells are potent antigen-presenting cells for microbial superantigens.

1992 ◽  
Vol 175 (1) ◽  
pp. 267-273 ◽  
Author(s):  
N Bhardwaj ◽  
S M Friedman ◽  
B C Cole ◽  
A J Nisanian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Small Subset ◽  
Cell Functions ◽  
Cell Responses ◽  
Antigen Presenting

Dendritic cells are a small subset of human blood mononuclear cells that are potent stimulators of several T cell functions. Here we show they are 10-50-fold more potent than monocytes or B cells in inducing T cell responses to a panel of superantigens. Furthermore, dendritic cells can present femtomolar concentrations of superantigen to T cells even at numbers where other antigen-presenting cells (APCs) are inactive. Although dendritic cells express very high levels of the major histocompatibility complex products that are required to present superantigens, it is only necessary to pulse these APCs for 1 hour with picomolar levels of one superantigen, staphylococcal enterotoxin B, to maximally activate T cells. Our results suggest that very small amounts of superantigen will be immunogenic in vivo if presented on dendritic cells.

Host γd T cells Exacerbate Experimental Acute Graft-Versus-Host Disease through Activation of Host Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3045-3045
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Chen Liu ◽  
D. Keith Bishop ◽  
James L.M. Ferrara
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Serum Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Full Intensity

Abstract Large numbers of T cells bearing γd T cell receptors are present in graft-versus-host disease (GVHD) target tissues. We investigated the potential role of host γd T cells during acute GVHD in a well-characterized GVHD model following full intensity conditioning (11 Gy TBI). BM and spleen T cells from BALB/c (H2d) donors were transplanted into wild type (wt) B6, aß T cell deficient B6 (aß −/−) or γd T cell deficient B6 (γd −/−) hosts. γd −/− hosts demonstrated significantly better day 35 survival (85%) than wt (40%) or aß−/− hosts (18%) (P<0.05). Reconstitution of γd −/− B6 hosts with B6 type γd T cells 24 hr prior to BMT restored lethal GVHD (50 % day 35 survival). In vivo, γd −/− B6 hosts demonstrated at least a five fold reduction in donor T cell expansion and cytokine production. In vitro, T cells proliferated less when co-cultured with allogeneic γd −/− dendritic cells (DCs) than with wt DCs (40,127 ± 1634 vs. 72,503 ± 1296, P<0.05). BM-derived DCs cultured with γd T cells caused greater proliferation of allogeneic T cells than DCs cultured with aß T cells (15.1 ± 21 x 104 vs. 5.1 ± 1.2 x 104, P<0.05). We next tested the effect of γd T cells on host DCs in vivo using a model system in which only the DCs injected prior to BMT expressed the alloantigen that stimulated the GVHD reaction. MHC Class II −/− B6 mice that had been depleted of γd T cells were given 11 Gy TBI and injected one day prior to BMT with B6 DCs that had been co-cultured either with γd T cells or with medium. On day 0 both groups of recipient mice were injected with BM plus splenic T cells from allogeneic bm12 donors. On day +5, CD4+ donor T cells expanded four times more in recipients of DCs co-cultured with γd T cells than in recipients of control DCs and serum levels of TNF-a were significantly higher (36.7 + 6.8 vs. 21.3 + 3.7 pg/ml, P<0.05). Together these data demonstrate that γd T cells amplify the stimulatory function of host DCs and increase the severity of GVHD, suggesting that a new therapeutic target for the prevention of the major BMT toxicity.

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.

Donor Dual TCR T Cells Preferentially Expand and Mediate Pathologic Alloreactivity in Acute Graft Versus Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1972-1972
Author(s):  
Gerald P. Morris ◽  
Geoffrey L Uy ◽  
David L Donermeyer ◽  
Paul M Allen ◽  
John F. DiPersio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Thymic Selection ◽  
Cell Repertoire ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 1972 The nature of the T cell repertoire mediating pathologic in vivo alloreactivity is an important question for understanding the development of acute graft-versus-host disease (aGvHD) following clinical allogeneic transplantation. We have previously demonstrated that the small proportion of T cells that naturally express 2 T cell receptors (TCR) as a consequence of incomplete TCRa allelic exclusion during thymic development contribute disproportionately to the alloreactive T cell repertoire, both in vitro and in vivo in a mouse model of graft versus host disease (GvHD) (J. Immunol., 182:6639, 2009). Here, we extend these findings to human biology, examining dual TCR T cells from healthy volunteer donors (n = 12) and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) (n = 19). Peripheral blood was collected at day 30 post-HSCT or at the time of presentation with symptomatic acute GvHD. Dual TCR T cells were measured in peripheral blood by pair-wise staining with 3 commercially-available and 2 novel TCRa mAbs. Dual TCR T cells were consistently and significantly expanded in patients with symptomatic aGvHD, representing 5.3±3.8 % of peripheral T cells, compared to 1.7±0.8 % of T cells in healthy controls (p < 0.005) (Figure 1). There was no correlation between dual TCR T cell frequency and GvHD severity. Furthermore, sequential analysis of peripheral blood in 2 patients demonstrated expansion of dual TCR T cells concurrent with the development of aGvHD (Figure 2). Dual TCR T cells from patients with symptomatic aGvHD demonstrated increased expression of CD69 as compared to T cells expressing a single TCR, indicative of preferential activation of dual TCR T cells during aGvHD. Similarly, dual TCR T cells isolated from patients with symptomatic aGvHD demonstrate increased production of IFN-g ex vivo, indicative of the ability to mediate pathogenic alloreactive responses. Dual TCR T cell clones isolated from healthy donors and patients post-HSCT by single cell FACS sorting demonstrate alloreactive responses against a range of allogeneic cell lines in vitro. We propose that the increased alloreactivity of dual TCR T cells results from the less stringent thymic selection for secondary TCR, and thus provides a link between thymic selection, the TCR repertoire, and alloreactivity. These findings may lead to simple ways of phenotypically identifying specific T cells predisposed to inducing aGvHD for subsequent examination of T cell repertoires and functional studies. Furthermore, these data suggest that dual TCR T cells represent a potential predictive biomarker for aGvHD and a potential target for selective T cell depletion in HSCT. Disclosures: No relevant conflicts of interest to declare.

Dendritic cell–activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3970-3978 ◽  
Author(s):  
Yi Zhang ◽  
Gerard Joe ◽  
Jiang Zhu ◽  
Richard Carroll ◽  
Bruce Levine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Antitumor Effects ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft versus host disease (GVHD) is triggered by host antigen-presenting cells (APCs) that activate donor T cells to proliferate and differentiate, but which APC-activated donor T-cell subsets mediate GVHD versus beneficial antitumor effects is not known. Using a CD8+ T cell–dependent mouse model of human GVHD, we found that host dendritic cell (DC)–induced CD44hiCD8+ effector/memory T cells were functionally defective in inducing GVHD, whereas CD44loCD8+ naive phenotype T cells were extremely potent GVHD inducers. Depletion of CD44loCD8+ T cells from host DC-stimulated T cells before transplantation prevented GVHD without impairing their antitumor activity in vivo. Compared with CD44loCD8+ T cells, CD44hiCD8+ T cells expressed high levels of Fas and were efficiently deleted in vivo following transplantation. These results suggest that ex vivo allogeneic DC stimulation of donor CD8+ T cells may be useful for the prevention of GVHD and for optimizing antitumor therapies in vivo.

scholarly journals ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist

2020 ◽  
Vol 12 (564) ◽  
pp. eaay4799
Author(s):  
Djamilatou Adom ◽  
Stacey R. Dillon ◽  
Jinfeng Yang ◽  
Hao Liu ◽  
Abdulraouf Ramadan ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Cell Phenotype ◽  
Murine Models ◽  
Host Disease ◽  
Graft Versus Host

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.

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