scholarly journals 13 Antigen presenting cells in the liver recruite activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease

2003 ◽  
Vol 9 (2) ◽  
pp. 67
Author(s):  
Y. Zhang ◽  
W.D. Shlomchik ◽  
G. Joe ◽  
J. Louboutin ◽  
J. Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2227-2234 ◽  
Author(s):  
Britt E. Anderson ◽  
Jennifer M. McNiff ◽  
Dhanpat Jain ◽  
Bruce R. Blazar ◽  
Warren D. Shlomchik ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Dominant Role ◽  
Chronic Gvhd ◽  
Antigen Presenting Cells ◽  
Target Tissue ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

AbstractThe application of allogeneic stem cell transplantation (alloSCT) is limited by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different requirements for initiation and pathogenesis mechanisms. In prior studies we demonstrated that residual host antigen-presenting cells (APCs) were required to initiate acute GVHD (aGVHD) mediated by CD8 T cells. In contrast, here we demonstrate that either donor or host APCs can initiate CD4-mediated GVHD in a model that has features of chronic GVHD (cGVHD). Both donor and host APCs must provide CD80/86-dependent costimulation to elicit maximal cGVHD, and there is no GVHD when both donor and host lack CD80/86. Finally, we were surprised to find that, although either donor or host APCs are sufficient to stimulate skin cGVHD, donor APCs play a dominant role in intestinal cGVHD. Both CD40 and CD80/86 are critical for donor APC function in intestinal cGVHD, but only CD80/86 is required for skin cGVHD. Thus, there are target-tissue–specific differences in APC requirements. These results identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD. They further highlight donor APCs as additional targets for GVHD therapy.

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.

Nuclear Translocation of RelB within Host and Donor Antigen Presenting Cells Is Critical for the Initiation and Maintenance of Acute Graft-Versus-Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 455-455 ◽  
Author(s):  
Kelli MacDonald ◽  
Rachel Kuns ◽  
Vanessa Rowe ◽  
Alistair Don ◽  
Edward Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Nuclear Translocation ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Clinical Scores ◽  
Antigen Presenting

Abstract Either donor or host antigen presenting cells (APC) are sufficient for the initiation of CD4 dependent graft versus host disease (GVHD). However the molecular transcription pathways within APC required for this effect are unknown. The NF-kB/Rel family member RelB is associated with dendritic cell (DC) maturation and is critical for the induction of potent APC function. DC from RelB−/− mice had markedly reduced levels of CD40 and to a lesser extent CD80/CD86 following in vitro activation. Following total body irradiation, the number of residual splenic DC with nuclear RelB was increased 5-fold relative to untreated mice. We therefore examined the role of RelB within donor and host APC in GVHD utilizing two well established bone marrow transplant models of CD4-dependant GVHD. To study the requirement of RelB within host APC we generated chimeric mice by transplanting wild-type (wt) or RelB−/− B6 bone marrow into irradiated wt B6 mice. Following immune reconstitution 4–6 months later, the number and frequency of DC (CD11chi and CD11cdimB220+) was equivalent in RelB−/− and RelB+/+ chimeras, although RelB−/− chimeras were specifically deficient in CD11chiCD4+ DC. Chimeras were subsequently transplanted with allogeneic Balb/c bone marrow and purified T cells. The absence of RelB within host APC significantly improved survival (survival day 60: 83% v 19%, P< .0001) and GVHD clinical scores were significantly reduced in RelB−/− chimeras for the first 4 weeks after transplant but subsequently rose to levels equivalent to those in surviving RelB+/+ chimeras. All RelB−/− and RelB+/+ chimeras that received syngeneic grafts survived without clinical evidence of GVHD. Sera from RelB−/− chimera recipients of allogeneic grafts contained reduced IFNg (117 ± 23 vs 253 ± 45 pg/ml; P< 0.02) and increased IL-5 (358 ± 105 vs 112 ± 20 pg/ml; P<0.05) compared to RelB+/+ chimera recipients (mean ± SE). Furthermore, CD4 T cells purified from the spleens of RelB−/− chimera recipients produced 2.6 fold more IL-4 (451 ± 31 vs 168 ± 17 pg/ml; P=0.01) than those from RelB+/+ chimera recipients. Taken together these data suggest the absence of nuclear RelB translocation within host APC abrogates GVHD and this is associated with the induction of donor Th2 differentiation. To study the role of RelB within donor APC we transplanted wt or RelB−/− B6 bone marrow and wt purified T cells into irradiated B6D2F1 recipients. In this model, GVHD severity was identical for the first 4 weeks after transplant but subsequently GVHD clinical scores in the recipients of RelB−/− donor APC returned toward levels seen in syngeneic recipients (clinical scores at day 49: 1.0 ± 0.6; n=6 vs 3.75 ± 0.4; n=6; RelB−/− vs RelB+/+P=0.01). This attenuation of acute GVHD in recipients of RelB−/− donor-derived APC was associated with the reconstitution of donor DC on day 21. These data suggest the inhibition of the nuclear RelB translocation within APC represents a potential new therapeutic target for the prevention of allograft rejection and GVHD.

scholarly journals Functional Contributions of Antigen Presenting Cells in Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao Hong ◽  
Rong Jin ◽  
Xiaoqiu Dai ◽  
Xiaoming Gao
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Immune Cells ◽  
Acute Gvhd ◽  
Antigen Presenting Cells ◽  
Hematopoietic Stem ◽  
Dominant Mechanism ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Chronic graft-versus-host disease (cGVHD) is one of the most common reasons of late non-relapse morbidity and mortality of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). While acute GVHD is considered driven by a pathogenic T cell dominant mechanism, the pathogenesis of cGVHD is much complicated and involves participation of a variety of immune cells other than pathogenic T cells. Existing studies have revealed that antigen presenting cells (APCs) play crucial roles in the pathophysiology of cGVHD. APCs could not only present auto- and alloantigens to prime and activate pathogenic T cells, but also directly mediate the pathogenesis of cGVHD via multiple mechanisms including infiltration into tissues/organs, production of inflammatory cytokines as well as auto- and alloantibodies. The studies of this field have led to several therapies targeting different APCs with promising results. This review will focus on the important roles of APCs and their contributions in the pathophysiology of cGVHD after allo-HSCT.

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.

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.

Graft-Versus-Host-Disease Recruits Both Monocyte and Pre-Conventional Dendritic Cell-Derived Tissue Antigen Presenting Cells Independent Of CCR2 and CCR6

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4463-4463
Author(s):  
Sarah Morin-Zorman ◽  
Christian Wysocki ◽  
Catherine Matte-Martone ◽  
Kathryn W Juchem ◽  
Hung Sheng Tan ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Blood Monocytes ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Antigen Presenting

Graft-versus-host disease (GVHD) limits the broader application of allogeneic hematopoietic stem cell transplantation. In prior studies we defined roles for both host and donor-derived antigen presenting cells (APCs) in the activation of alloreactive donor T cells and in promotion of GVHD. While initial T cell activation in GVHD occurs predominantly in secondary lymphoid organs, we have consistently observed MHCII+ donor-derived APCs, including dendritic cells (DCs), in histopathologic GVHD lesions, frequently adjacent to infiltrating T cells, suggesting they have a role in local GVHD reactions. Donor-derived tissue APCs (t-APCs), including tissue-DCs (t-DCs) could activate donor T cells through indirect or cross-presentation of host antigens, produce chemokines that recruit other effectors, and elaborate inflammatory mediators or suppressors of inflammation. We first characterized t-DC subsets in the skin and bowel of GVHD-affected mice. 129 (H-2b) hosts were irradiated and reconstituted with B6 (H-2b) BM with or without CD4+ and CD8+ T cells to induce GVHD and analyzed mononuclear cells from skin and bowel approximately 4 weeks post transplant. In skin, both main dermal DC populations (CD11b+ and CD103+) were significantly increased in GVHD mice as compared to BM alone controls, though the ratios of CD11b+: CD103+ DCs were similar. In the bowel lamina propria, the ratios of CD11b+CD103- to CD11b+CD103+ were increased in GVHD mice in the colon but were similar to that in BM alone controls in the small bowel. We next studied the roles of CCR6 and CCR2 in the recruitment of donor-derived APCs to skin and bowel. We transplanted mice with CCR6-/- BM in competition with wild type (wt) BM and found that the contribution of each to skin and bowel APCs matched their contributions to myeloid hematopoiesis in BM, spleen and blood, indicating that CCR6 is not required. To study the role of CCR2 we first compared mice transplanted with either wt or CCR2-/- BM with wt T cells. Despite having a profound reduction in blood monocytes, all skin and bowel t-APC subsets were present in CCR2-/- recipients, indicating that CCR2 is not required for t-APC recruitment in contrast to its role in many other models of inflammation. However, CD103+ DCs were more prevalent relative to CD11b+ DCs, consistent with a pre-cDC origin. Despite monocytopenia, recipients of CCR2-/- BM developed clinical GVHD; histology data is being analyzed and will be presented. To better define the contributions of CCR2 to t-APC recruitment and to determine monocyte versus pre-cDC origin of t-DCs, we transplanted mice with CCR2-/- BM in competition with wt BM and compared ratios of BM and blood precursors (pre-cDCs and monocytes) to t-DC ratios. For CD103+ DCs, wt/KO ratios matched the ratios of general myeloid hematopoiesis and pre-cDCs, indicating a pre-cDC origin. For CD11b+CD103- DCs, the ratio of wt/KO matched that in blood monocytes. We further subsetted CD11b+ t-DCs based on the expression of Ly6C, MAR1, CD64 and CD24, used to differentiate pre-cDC from mono-derived DCs in other organs, and did not identify any population with wt/KO ratios that did not match that of the general CD11b+ DC population, suggesting that most if not all CD11b+ t-DCs are of monocyte origin. Experiments are underway examining the role of CX3CR1 in t-APC recruitment and these data will be presented. Disclosures: No relevant conflicts of interest to declare.

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.

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