Higher Numbers of Circulating Dendritic Cells and T-Cells Predict Response to Extracorporeal Photopheresis in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1183-1183
Author(s):  
Cynthia R. Giver ◽  
Mojtaba Akhtari ◽  
Amelia A. Langston ◽  
H. Jean Khoury ◽  
Christopher R. Flowers ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Numbers ◽  
Hla Dr

Abstract Background: Therapeutic options for steroid-refractory chronic graft-versus-host-disease (cGVHD) are limited. Extracorporeal photopheresis (ECP) is a photoimmune therapeutic modality to treat cGVHD that is tolerated relatively well, but its mechanism has not been fully defined. One model for the mechanism of ECP in cGVHD is dendritic cell (DC) depletion and T-cell modification (Alcindor, T, et al., BLOOD2001, 98:1622). We tested this hypothesis by determining the numbers of circulating DCs and T-cells prior to ECP and during therapy in patients with cGVHD, and correlating cell numbers with response. Methods: This study was IRB approved. We studied 25 adult pts (median age 43 yrs, range 23–71) with histories of hematological malignancies including NHL (n=7), AML (n=5), CML (n=5), ALL (n=3), MDS (n=3), Hodgkin’s lymphoma (n=1), and CLL (n=1), who developed cGVHD after allogeneic, HLA-matched HPCT. Ten pts had progressive, 9 pts had de novo, and 6 pts had interrupted cGVHD. Initial treatment of cGVHD included corticosteroids in all pts. At the time of ECP initiation, pts were either dependent upon corticosteroids for control of cGvHD (21 pts), or steroid-intolerant (4 pts). No pts had received ECP prior to this study. ECP was administered 2 consecutive days every week for the first 2 months, two times a week every other week for 2 months, and then two times a week once a month. In addition to ECP, pts received steroids (21), MMF (n=13), FK506 (n=15), cyclosporine (n=3), MTX (n=3), rapamycin (n=1), rituximab (n=1) or pentostatin (n=1). Sites of cGVHD included skin (n=25), oropharynx (n=7), liver (n=5), gut (n=4), lung (n=1), and eye (n=1). A good response was defined as having > 50% reduction in the corticosteroid dose within 4 months of starting ECP, with improved or stable lesions on skin and other sites. For steroid-intolerant pts, clinical parameters such as improvement in skin condition were used to identify responders. Peripheral blood mononuclear cells were analyzed before ECP began and every 2 months during ECP therapy. The numbers of plasmacytoid DCs (pDC, Lin− CD123+ CD11c− HLA-DR+), myeloid DCs (mDC, Lin− CD123− CD11c+ HLA-DR+), and CD4+ and CD8+ T-cells in blood were determined by flow cytometry. Results: Median follow up of the 25 pts was 47.1 months (range, 8.6–90.9) from the time of transplant. The median number of ECP treatments was 26 (range 2–68). Fourteen pts (56%) had good response, and 11 were non-responders. The median time between HPCT and onset of cGVHD was similar for responders (8.6 months, range 3.3–34.7) and non-responders (6.1, range 3.4–43.8, p=0.52). The median time between HPCT and ECP was also similar for the two groups (32.3 months, range 13.1–60.0, vs. 21.9 months, range 4.1–47.5, respectively, p=0.12). Responders had an estimated 2-yr survival of 88% after starting ECP, vs 18% for non-responders (p=0.004). Two responders died at 11.2 and 31.2 months after starting ECP, compared with 7 non-responders (median 4.4 months, range 2.8–22.1). Non-responders had a relative risk of death of 11.6 compared with responders (p=0.022). Average prednisone doses for responders and non-responders were comparable, averaging 24.3 and 41.8 mg/day, respectively (p=0.11). Responders had higher baseline numbers of pDCs (average 5.8 vs. 0.6 cells/mcL, p=0.025) and mDCs (average 15 vs. 3.8 cells/mcL, p= 0.01) compared with non-responders. Baseline CD4+ T-cell numbers were higher in responders compared with non-responders (average 623 vs. 178 cells/mcL, p=0.005), as were CD8+ T-cell numbers (712 vs. 251 cells/mcL, p=0.047). Contrary to the original hypothesis, there were no consistent changes in the numbers of circulating DCs and T-cells among responders over a 12-month period. Receiver-operator characteristics (ROC) analysis showed that baseline numbers of blood mDCs of >3.7 cells/mcL prior to ECP had 79% sensitivity and 82% specificity to predict response of cGvHD patients to ECP. Conclusion: Our results demonstrate that higher numbers of circulating DCs and T-cells predict response to ECP in pts with cGVHD. Response to ECP was significantly associated with improved survival in univariate and multivariate analyses (p<0.03). Our findings support a newer model for the mechanism of response to ECP therapy, involving interactions between donor-derived DCs and donor T-cells. The generation of regulatory T-cells by dendritic cells presenting antigens from apoptotic bodies will be discussed.

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.

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.

scholarly journals ICOSL+ Plasmacytoid Dendritic Cells As Biomarker and Inducer of Graft-Versus-Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 355-355
Author(s):  
Djamilatou Adom ◽  
Abdulraouf Ramadan ◽  
Kushi Kushekhar ◽  
Sophie Paczesny
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Costimulatory Molecule ◽  
Activation Markers ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (GVHD) remains one of the leading causes of death post allogeneic hematopoietic cell transplantation (HCT). Gastrointestinal GVHD (GI-GVHD), the most fatal type of GVHD, would benefit from additional biomarkers that are therapeutic targets. Using state-of-the-art quantitative proteomics we previously identified and validated an increased CD4+CD146+ T cell population in GI-GVHD patients. This population expressed a Th1 and Th17 phenotype and was induced by Inducible COStimulator (ICOS), a critical costimulatory molecule for the development of pathogenic Th17 (Li W. et al, J. Clin. Invest. Insights, 2016). ICOS binds its ligand, ICOSL, which is expressed on dendritic cells (DCs) that prime naïve T cells to initiate immune responses. This prompted us to examine ICOSL expression on the two blood DCs subsets that can be identified in human peripheral blood: Lineage-HLADR+CD11c+ myeloid DCs (mDCs) and Lineage-HLADR+CD123+ plasmacytoid DCs (pDCs). Using the same cohort of patients aforementioned, the frequency of ICOSL was significantly higher on pDCs in 64 GI-GVHD patients when compared to 22 non-GVHD enteritis patients, 35 skin GVHD patients, and 39 patients without GVHD (Figure 1). The numbers and frequencies of total DCs, mDCs and pDCs were similar between groups. The growth factor fms-related tyrosine kinase 3 ligand (Flt3l) is necessary for the development and differentiation of pDCs, and the transcription factor, Stat3, is required for Flt3l-dependent dendritic cell differentiation in mice. The role of pDCs in acute GVHD is still controversial (tolerogenic or initiator of GVHD depending on the murine model), and confirmatory studies about their functions are necessary before a therapeutic approach based on this mechanism can be contemplated. Based on the patients' data and previous knowledge, we hypothesized that absence of ICOSL signaling in donor DCs would protect against GVHD through Flt3l, Stat3, or both. We first found that knocking out (KO) ICOSL in the donor bone marrow (BM) extended survival compared to wild-type (WT) mice in the major mismatch (B6, H-2b à BALB/c, H-2d) experimental HCT model, while recipients of Stat3KO BM did not show any difference in GVHD mortality (Figure 2A). We also found a significant decrease of Flt3l levels in plasma collected at day 3 from ICOSLKO BM recipients compared to WT mice (Figure 2B). We then analyzed the recipients' infiltrating intestinal immune cells at day 10 post-HCT for the infiltration of pDCs and pathogenic Th17 cells. We found significantly lower frequencies of intestinal pDCs (CD11b-CD11c+B220+CD103+) (Figure 2C), and intestinal T cells coexpressing interferon (IFN)g and IL-17 (Figure 2D) in recipients of ICOSLKO BM compared to recipients of WT BM. Absolute counts of these two populations followed the same trend (data not shown). To confirm these data were not strain-specific, we performed similar analyses in the haplo-identical (B6, H-2b à B6D2F1, H-2d) experimental model showing similar outcomes for pDCs and IFNγ+IL-17+ T cells frequencies and counts in recipients of ICOSLKO BM compared to recipients of WT BM. Importantly, and in contrast to human T cells, CD146 is not expressed on naïve murine T cells and thus cannot be measured in vivo in acute GVHD models. Transcriptome analyses by Nanostring technology (Immunology panels) comparing 14 days post-HCT of sorted pDCs from ICOSLKO BM versus WT haplo-identical recipients showed increased expression of key molecules required for development (Itgax, Nos2, Socs1, Tcf4 and Bst2), costimulation (Cd80, Cd48, Cd74 and Cd86), and function (Tyrobp, Ikbkg, Nod2 and Irf7) of pDCs (Figure 3A). Lastly, we found increased T cell activation markers including Prf1, Il17a, eomes in sorted CD4+ T cells from ICOSLKO BM compared to WT recipients (Figure 3B). We conclude that early quantification of ICOSL+ pDCs frequency may allow identification of patients at risk of GI-GVHD development. Targeting ICOSL may represent a new avenue to treat acute GVHD. Disclosures Paczesny: Viracor IBT Laboratories: Patents & Royalties.

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 Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2216-2224
Author(s):  
David Spaner ◽  
Xiaofang Sheng-Tanner ◽  
Andre C. Schuh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Scid Mice ◽  
Control Mechanisms ◽  
Activated T Cells ◽  
Host Disease ◽  
Immunodeficient Mice ◽  
Graft Versus Host

Acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation is associated with impaired deletion and anergy of host-reactive T cells. To elucidate the immunoregulatory events that may contribute to such dysregulated T-cell responses in GVHD, we studied superantigen (SAg) responses after adoptive T-cell transfer into severe combined immunodeficient (SCID) mice. SAg responses are normally regulated by mechanisms involving deletion and anergy, with SAg-reactive T cells typically being deleted rapidly in vivo. In a SCID mouse model of GVHD, however, allogeneic host SAg-reactive T cells were not deleted rapidly, but rather persisted in increased numbers for several months. Moreover, depending on the timing of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be demonstrated following the adoptive transfer of syngeneic T cells into SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of weakly reactive T cells after adoptive transfer and SAg stimulation. When transferred alone, KJ1-26.1+ T cells demonstrated impaired deletion and anergy. In the presence of more strongly staphylococcal enterotoxin B (SEB)–reactive T cells, however, KJ1-26.1+ T cells were regulated normally, in a manner that could be prevented by inhibiting the effects of more strongly SEB-reactive cells or by increasing the level of activation of the KJ1-26.1+ T cells themselves. We suggest that the control mechanisms that normally regulate strongly activated T cells in immunocompetent animals are lost following adoptive transfer into immunodeficient hosts, and that this impairment contributes to the development of GVHD.

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