Notch Signaling in Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-14-SCI-14
Author(s):  
Ivan Maillard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Alloreactive T Cells ◽  
Donor T Cells ◽  
Notch Inhibition

Abstract SCI-14 Notch is a highly conserved signaling pathway with multiple functions in health and disease. In the hematopoietic system, Notch was first described for its essential role at early stages of T cell development in the thymus and for its involvement in T cell acute lymphoblastic leukemia. In addition, Notch is being increasingly recognized as a potent regulator of antigen-driven mature T cell responses with context-dependent effects. These effects are influenced by the regulated expression of Jagged and Delta-like Notch ligands in antigen-presenting cells under the control of Toll-like receptors and other innate signals. We are investigating the importance of the Notch pathway in T cell alloimmunity in the setting of allogeneic bone marrow or peripheral blood stem cell transplantation (allo-BMT). After allo-BMT, alloimmune T cell responses mediate beneficial graft-versus-tumor (GVT) activity as well as detrimental graft-versus-host disease (GVHD). Using the pan-Notch inhibitor DNMAML and other genetic models of Notch inhibition, we have discovered an essential function for Notch signaling in donor-derived alloreactive T cells. In multiple mouse models of allo-BMT, infusion of Notch-deficient T cells as compared to wild-type T cells led to dramatically reduced GVHD severity and lethality. This effect was apparent for both CD4+ and CD8+ T cells and did not involve global immunosuppression, since Notch-deficient T cells proliferated normally and expanded in host lymphohematopoietic organs. However, Notch-deficient donor T cells failed to accumulate in the gut, a key GVHD target organ, and produced markedly decreased amounts of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-2. In parallel, Notch inhibition was associated with increased accumulation of FoxP3+CD4+ T cells. Decreased cytokine production could not be explained by a classical T helper differentiation defect. In contrast to their defective induction of GVHD, Notch-deficient T cells remained capable of mediating cytotoxic and anti-tumor responses both in vitro and in vivo, leading to preserved GVT activity even against large numbers of tumor cells. We are currently investigating the molecular and cellular mechanisms of Notch action in alloreactive T cells. We are also exploring the role of individual Notch receptors and ligands at the alloimmune synapse in vivo. Altogether, our findings identify Notch inhibition in donor T cells as a novel strategy to induce beneficial immunomodulation rather than global immunosuppression after allo-BMT. Disclosures: No relevant conflicts of interest to declare.

Attenuated Acute Graft-Versus-Host Disease Following Allogeneic Stem Cell Transplantation In the Absence of RORγt.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3742-3742
Author(s):  
LeShara M Fulton ◽  
Michael J Carlson ◽  
James Coghill ◽  
Michelle L. West ◽  
Angela Panoskaltisis-Mortari ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Abstract 3742 CD4+ T helper (Th) cells play a critical role in the development of Graft-versus-Host Disease (GvHD). The relative contributions of particular Th subsets to GVHD pathogenesis, however, are incompletely understood. In order to clarify the contribution of the Th17 subset to GVHD induction, we made use of mice knocked out at the RORgt locus (RORgt−/−), a transcription factor crucial for Th17 polarization. Methods: Haplotype matched and complete MHC mismatched murine HSCT models were used. For the haploidentical model C57BL/6 (H-2b, B6) mice served as donors while C57BL/6 × DBA2 F1 (H-2bxd, B6D2) mice functioned as recipients. Effector T cells (Teffs) were isolated from the spleens of wild type (WT) B6 and RORgt knockout mice backcrossed 7–8 generations onto a B6 background. B6D2 mice were lethally irradiated with 900 rads on day -1 and injected intravenously with 4 × 106 Teffs from WT or RORgt−/− mice supplemented with 3 × 106 WT T cell depleted bone marrow cells (TCD BM) on day 0. For the completely MHC mismatched model, BALB/c mice (H-2d) were lethally irradiated with 800 rads on day -1 and administered 5 × 105 WT or RORgt−/− Teffs supplemented with 5 × 106 B6 TCD BM on day 0. Results: B6D2 mice that received RORgt−/− Teffs displayed significantly attenuated GvHD, recovering from weight loss by day +31 and demonstrating 100% survival on day +60. Conversely, mice that received WT Teffs showed intense disease progression with 100% mortality by day +31 (Figure A, p<0.0001 for survival comparison between WT and RORgt−/− recipients using Fisher's exact test). Similar results were seen using the completely MHC mismatched model, with superior overall survival noted in those animals receiving RORgt −/− Teffs (put in p value here). Recipients of RORgt −/− T cells demonstrated statistically significant decreased TNF in serum compared to WT recipients (Figure B, p=0.001 comparing WT and RORgt−/− recipients using student's t test). Interestingly, despite the decreased severity of GvHD, serum concentrations of IFN-g were increased in recipients transplanted with RORgt −/− T cells. Chimerism studies post-transplant revealed complete donor reconstitution in recipients of both RORgt−/− and WT Teffs. Donor Teffs isolated from recipient livers post-transplant consistently demonstrated an activated phenotype, with low L selectin and high CD25 expression. Conclusions: T cell expression of the Th17 transcription factor, RORgt, is critical for the development of lethal GvHD following allogeneic stem cell transplantation in both the haploidentical and MHC complete mismatch models. GvHD attenuation in the absence of RORgt is not the result of an inability for donor T cells to undergo activation or to engraft in vivo. Interestingly, the absence of RORgt from donor T cells led to enhanced IFN-g in serum. Thus, in vivo, the Th17 pathway is critical for the induction of GvHD. Disclosures: No relevant conflicts of interest to declare.

In Vivo Blockade of Individual Notch Ligands and Receptors Provides a New Targeted Therapeutic Approach In Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 819-819
Author(s):  
Ivy T Tran ◽  
Ashley R Sandy ◽  
Alexis Carulli ◽  
Gloria T Shan ◽  
Vedran Radojcic ◽  
...  
Keyword(s):  
T Cells ◽  
Notch Signaling ◽  
Gamma Secretase ◽  
Notch Receptors ◽  
Alloreactive T Cells ◽  
Donor T Cells ◽  
Notch Inhibition ◽  
Total Body ◽  
Notch Ligands

Abstract Abstract 819 Notch signaling is a cell-cell communication pathway with multiple functions in health and disease. Notch ligands of the Delta-like (Dll1, 3, 4) or Jagged (Jagged1, 2) family interact with one of four mammalian Notch receptors (Notch1-4), leading to proteolytic activation of the receptors by gamma-secretase. We have discovered a critical role for Notch signaling in the differentiation of pathogenic host-reactive T cells during graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). Expression of the pan-Notch inhibitor DNMAML in donor T cells led to markedly reduced GVHD severity, without causing global immunosuppression (Blood 2011, 117(1): 299–308). These findings identify Notch signaling in alloreactive T cells as an attractive therapeutic target after allo-BMT. To explore preclinical strategies of Notch blockade in GVHD, we first assessed the effects of systemic pan-Notch inhibition with gamma-secretase inhibitors. In the B6 anti-BALB/c MHC-mismatched model of allo-BMT, administration of the gamma-secretase inhibitor dibenzazepine was as efficient as genetic strategies at blocking Notch target gene expression and production of inflammatory cytokines in donor T cells (IFN-γ, TNF-α, IL-2). However, dibenzazepine induced severe gastrointestinal toxicity after total body irradiation due to inhibition of both Notch1 and Notch2 in the gut epithelium. To avoid these side effects, we hypothesized that targeting individual Notch receptors or ligands could provide safe therapeutic Notch blockade after allo-BMT. Among the four mammalian Notch receptors (Notch1-4), donor alloreactive T cells expressed Notch1 and Notch2. Host dendritic cells expressed Notch ligands of the Jagged and Delta-like (Dll) families, with markedly increased Dll4 but not Jagged1/2 transcripts after total body irradiation. This suggested that blockade of Notch1 and/or Notch2 in T cells or Delta-like Notch ligands in dendritic cells could abrogate GVHD. To explore this possibility, we used specific monoclonal antibodies to neutralize Notch receptors and ligands in vivo after allo-BMT (Nature 2006, 444(7122):1083–7; Nature 2010, 464(7291): 1052–7). Combined blockade of Notch1 and Notch2 in vivo reduced the production of key inflammatory cytokines by alloreactive CD4+ and CD8+ T cells to a similar extent as DNMAML-mediated pan-Notch inhibition. Inhibition of Notch1 alone led to a large decrease in cytokine secretion, indicating that Notch1 is a dominant non-redundant Notch receptor in alloreactive T cells. Consistently, transplantation of Notch1-deficient but not Notch2-deficient B6 T cells allowed for decreased GVHD and improved survival in BALB/c recipients, similarly to global Notch inhibition by DNMAML. We then studied the consequences of inhibiting Dll1, Dll4 or both Dll1/Dll4 Notch ligands during acute GVHD. Combined Dll1/Dll4 blockade was as potent as DNMAML expression in decreasing cytokine production by alloreactive T cells, demonstrating that Delta-like and not Jagged ligands are the key Notch agonists at the alloimmune synapse. Dll4 inhibition was superior to Dll1 blockade in reducing cytokine production, abrogating GVHD, and prolonging recipient survival. Importantly, combined Dll1/Dll4 inhibition provided long-term protection against GVHD morbidity and mortality, while avoiding severe gastrointestinal side effects from Notch inhibition. Protection was observed even upon transient Dll1/Dll4 blockade during 1–2 weeks after transplantation. Altogether, our data suggest that Notch1 and Dll4 preferentially interact during alloreactive T cell priming and identify novel strategies to safely and efficiently target individual elements of the Notch pathway after allo-BMT. Humanized antibodies against Notch receptors and ligands were designed to block both mouse and human proteins, thus our preclinical work could lead to new strategies for GVHD control in human patients. Disclosures: Shelton: Genentech Inc.: Employment. Yan:Genentech Inc.: Employment. Siebel:Genentech Inc.: Employment.

Notch Inhibition in Alloreactive CD4+ and CD8+ T Cells Blocks Graft-Versus-Host Disease by Inducing a Hyporesponsive Program with Features of T Cell Anergy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 340-340
Author(s):  
Ashley R Sandy ◽  
Jooho Chung ◽  
Ivy T Tran ◽  
Gloria T Shan ◽  
Ann Friedman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Ifn Gamma ◽  
Cell Compartments ◽  
Alloreactive T Cells ◽  
Notch Inhibition

Abstract Abstract 340 Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogeneic bone marrow transplantation (allo-BMT). We previously identified Notch signaling as an essential regulator of allogeneic CD4+ T cell responses mediating GVHD after allo-BMT. Alloreactive CD4+ T cells expressing the pan-Notch inhibitor DNMAML induced markedly less severe GVHD as compared to wild-type T cells, leading to improved survival of the recipients. Notch-deprived T cells had preserved in vivo expansion and cytotoxicity. However, alloreactive DNMAML CD4+ T cells produced markedly decreased amounts of multiple proinflammatory cytokines, including TNF-alpha, IFN-gamma, and IL-2. This was associated with increased expansion of Foxp3+ CD4+ T regulatory cells. Thus, Notch signaling is an attractive new therapeutic target to control GVHD without eliminating the anti-cancer activity of allo-BMT. To elucidate the mechanisms of Notch action in GVHD, we studied the effects of Notch inhibition in alloreactive CD4+ and CD8+ T cells using minor and major histocompatibility antigen-mismatched models of allo-BMT. In the B6 anti-BALB/b minor antigen-mismatched model, recipients of B6 T cells were protected from lethal acute GVHD upon DNMAML expression in the CD4+, CD8+ or both T cell compartments. In the B6 anti-BALB/c MHC-mismatched model, DNMAML CD4+ or CD8+ T cells transplanted alone or in combination induced significantly less GVHD and resulted in improved survival compared to wild-type T cells. Upon ex vivo restimulation with anti-CD3/CD28 antibodies, both CD4+ and CD8+ DNMAML alloreactive T cells had markedly decreased production of IFN-gamma. These findings suggest that Notch signaling has parallel functions in CD4+ and CD8+ T cells. We then studied expression of Tbx21 (encoding T-bet) and Eomes, the key transcription factors regulating Ifng transcription in CD4+ Th1 and CD8+ T cells, respectively. DNMAML alloreactive T cells had preserved amounts of Tbx21 mRNA and T-bet protein, and increased levels of Eomes transcripts and protein. These data differ from past reports indicating that Notch signaling controls T cell differentiation through direct regulation of Tbx21 and Eomes expression. Ex vivo restimulation of DNMAML CD4+ and CD8+ T cells with PMA (diacylglycerol analog) and ionomycin (calcium ionophore) rescued IFN-gamma production by both T cell compartments and partially restored IL-2 production by CD4+ T cells, suggesting abnormal signaling downstream of the T cell receptor. After anti-CD3/CD28 restimulation, DNMAML alloreactive T cells showed markedly decreased phosphorylation of Mek1 and Erk1/2, indicating defective Ras/MAPK activation. PMA was sufficient to rescue Erk1/2 activation. NFkB activity was also significantly impaired in alloreactive DNMAML T cells as assessed with a NFkB-luciferase reporter transgene. Abnormal responsiveness was acquired in vivo during alloreactive T cell priming, since naïve DNMAML T cells had preserved Ras/MAPK activation. Moreover, alloreactive Notch-deprived T cells had elevated levels of intracellular cAMP and increased expression of the anergy-associated genes, Dgka and Egr3. Thus, alloreactive DNMAML T cells had features reminiscent of T cell anergy. Given that in vivo proliferation in irradiated recipients and cytotoxicity of DNMAML alloreactive T cells were largely preserved, our data suggest a “split anergy” phenotype with differential effects on distinct T cell effector functions. Altogether, our results reveal a parallel role for Notch signaling in both the CD4+ and CD8+ T cell compartments that differ from all previous reports of Notch action in mature T cells. Understanding the role of Notch signaling in alloreactive T cells is essential for harnessing the therapeutic potential of Notch inhibition in GVHD. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Graft-Versus-Host Disease Causes the Failure of Donor Hematopoietic Progenitor Cells to Reconstitute Plasmacytoid Dendritic Cells That Promote Tolerance of Donor T Cells Against the Host

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 193-193
Author(s):  
Yuanyuan Tian ◽  
Lijun Meng ◽  
Hongshuang Yu ◽  
Ying Wang ◽  
Tien Bui ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Graft Versus Host ◽  
Effector Molecules ◽  
Gm Csf ◽  
Alloreactive T Cells ◽  
Donor T Cells

Promoting donor T cell tolerance to host non-hematopoietic tissues remains the ultimate therapeutic goal in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dendritic cells (DCs) play dual functions in regulating alloimmunity. DCs can elicit alloreactive T cell responses to mediate graft-versus-host disease (GVHD), but are also implicated in reducing GVHD. In patients, the depletion of plasmacytoid DCs (pDCs) from donor BM grafts resulted in GVHD acceleration. On the other hand, acute GVHD causes complete failure of donor pDC reconstitution after allo-HSCT, and low levels of donor pDC correlate with significantly increased GVHD severity. Thus, the impairment of pDC reconstitution by GVHD may be responsible for the dysfunctional immune regulation. Delineation of the mechanism involved may allow therapeutic intervention to reduce GVHD and improve the efficacy of allo-HSCT. In this study, we demonstrate that alloreactive T cells produce GM-CSF to impair reconstitution of donor pDCs by inhibiting Flt3 expression and its-regulated transcription programs in DC progenitor cells. Using murine GVHD model, we confirmed GVHD severely impaired reconstitution of both donor pDCs and conventional DCs (cDCs). Adoptive transfer of donor-type pDCs rather than cDCs prevented the occurrence of severe GVHD in mice, suggesting donor pDC reconstitution is important to restore tolerance of donor T cells against host tissues. Flt3 is required to induce pDC production through a successive differentiation pathway: HSC → multiple potential progenitors (MPP) → common DC progenitors (CDP) → precursor DCs (pre-DCs). GVHD mice produced significantly less MPP, CDP and pre-DCs compared to normal donor mice and allogeneic mice receiving T cell-depleted BM. Ex vivo culture with Flt3 ligand (Flt3L) showed that those MPP and CDP derived from GVHD mice dramatically decreased the capacity to produce pDCs. Thus, GVHD not only causes decreased numbers of MPP and CDP but also their intrinsic defect in producing pDCs. While both MPP and CDP gave rise to similar numbers of pDCs within 3 days of culture with Flt3L, MPP produced 40-fold more pDCs than CDP by day 9 of culture. This indicates the impairment in GVHD MPP may have much more profound long-term impact on pDC reconstitution than that in CDP. Based on surface expression of Flt3, normal MPP contained two subsets: CD135high MPP and CD135mod MPP. CD135high MPP produced 4-fold more pDCs than CD135mod MPP. As compared to CD135mod MPP, CD135high MPP expressed lower levels of Ink4 family genes, which are cyclin-dependent inhibitors restraining cell proliferation and survival, suggesting that CD135high MPP represent earlier stage differentiated progenitors with greater proliferative capacity. Intriguingly, although GVHD mice generated similar amount of CD135mod MPP as did normal mice, they failed to reconstitute highly proliferative CD135high MPP. Thus, the failure of donor pDC reconstitution may largely result from GVHD-mediated inhibition of CD135high MPP. Alloreactive T cells are known to produce high levels of effector molecules, such as IFN-γ, TNF-α, GM-CSF and other cytolytic molecules. We observed that GVHD effector T cells significantly reduced the production of pDCs from Flt3L-induced normal MPP. Blocking GM-CSF using neutralizing antibody but not other effector molecules markedly inhibited this repressive effect of GVHD T cells on pDC production. GM-CSF dose-dependently decreased the expression of Flt3 and its-regulated transcription factors Irf8 and Tcf4, which are important for development of functional pDCs. However, GM-CSF failed to inhibit the conversion of SiglecH+ pre-pDCs into pDCs. These data suggest that alloreactive T cells produce GM-CSF to block pDC reconstitution by targeting DC progenitors (e.g., MPP and CDP). Building on these findings, we established a novel optimized culture system to produce adequate numbers of SiglecH+ pre-pDCs. Adoptive transfer of these pre-pDCs prevented GVHD, leading to significantly improved overall survival of mice undergoing allo-HSCT. Our findings identify for the first time that selective restoration of donor pDCs early after allo-HSCT may represent an effective cellular therapy to prevent GVHD. Further delineation of the molecular pathway(s) involved in GVHD inhibition of DC progenitors may allow the development of novel approaches to circumvent mortality and morbidity associated with GVHD. Disclosures Zheng: Pfizer: Research Funding.

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 β2 integrins separate graft-versus-host disease and graft-versus-leukemia effects

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 954-962 ◽  
Author(s):  
Yaming Liang ◽  
Chen Liu ◽  
Julie Y. Djeu ◽  
Bin Zhong ◽  
Thorsten Peters ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Morbidity And Mortality ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Β2 Integrins

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins are critically important for leukocyte extravasation through vascular endothelia and for T-cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing the graft-versus-leukemia (GVL) effect. In murine allogeneic bone marrow transplantation models, we found that recipients of CD18−/− donor T cells had significantly less GVHD morbidity and mortality compared with recipients of wild-type (WT) donor T cells. Analysis of alloreactivity showed that CD18−/− and WT T cells had comparable activation, expansion, and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor T-cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that the in vivo GVL effect of CD18−/− donor T cells was largely preserved, because mortality of the recipients who received transplants of CD18−/− T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target β2 integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.

scholarly journals Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 299-308 ◽  
Author(s):  
Yi Zhang ◽  
Ashley R. Sandy ◽  
Jina Wang ◽  
Vedran Radojcic ◽  
Gloria T. Shan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Acute Gvhd ◽  
Cd4 T Cell ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Effector Molecules ◽  
Cell Responses ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4+ and CD8+ T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4+ T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4+ T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.

scholarly journals Prevention of Graft-Versus-Host Disease in Mice Using a Suicide Gene Expressed in T Lymphocytes

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4636-4645 ◽  
Author(s):  
José L. Cohen ◽  
Olivier Boyer ◽  
Benoı̂t Salomon ◽  
Rosine Onclercq ◽  
Frédéric Charlotte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Therapeutic Strategy ◽  
Suicide Gene ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Cell Pool ◽  
Ganciclovir Treatment

Abstract Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T 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&lt;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&lt;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&lt;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&lt;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.

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