Division rate and phenotypic differences discriminate alloreactive and nonalloreactive T cells transferred in lethally irradiated mice

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3156-3158 ◽  
Author(s):  
Sébastien Maury ◽  
Benoı̂t Salomon ◽  
David Klatzmann ◽  
José L. Cohen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Division Rate ◽  
Hematopoietic Stem ◽  
Phenotypic Differences ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Donor T Cells ◽  
Life Threatening ◽  
T Cell Transfer

Abstract After non-T-cell–depleted allogeneic hematopoietic stem cell transplantation (HSCT), both alloreactive and homeostatic signals drive proliferation of donor T cells. Host-reactive donor T cells, which proliferate on alloantigen stimulation, are responsible for the life-threatening graft-versus-host disease. Non–host-reactive donor T cells, which proliferate in response to homeostatic signals, contribute to the beneficial peripheral T-cell reconstitution. The elimination of alloreactive T cells is a major therapeutic challenge for HSCT and would greatly benefit from their specific identification. After T-cell transfer in lymphopenic recipients, the present results show that alloreactive T cells rapidly divided; up-regulated CD69, CD25, and CD4 molecules; and down-regulated CD62L. In contrast, nonalloreactive T cells started to divide later and did not up-regulate CD69, CD25, and CD4. Thus, these 2 cell populations can be effectively discriminated. This should facilitate the specific depletion of alloreactive T cells in allogeneic HSCT.

Absence of Inducible Costimulator (ICOS) on Alloreactive T Cells Reduces Graft-versus-Host-Disease While Leaving Graft-Versus-Tumor Activity Intact.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 592-592
Author(s):  
Vanessa M. Hubbard ◽  
Jeffrey M. Eng ◽  
Kartono H. Tjoe ◽  
Teresa Ramirez-Montagut ◽  
Stephanie J. Muriglan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Graft Versus Host ◽  
Cell Numbers ◽  
Alloreactive T Cells ◽  
Inducible Costimulator ◽  
Target Organs ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Inducible costimulator (ICOS) is a member of the B7 family that is expressed on activated and memory T cells and is involved in the regulation of TH1 and TH2 effector cytokine production after CD3/TCR stimulation. Studies with ICOS inhibition or ICOS−/− recipients have demonstrated prolonged allograft survival after heart or liver transplantation in animal models. To study the role of ICOS expression on alloreactive T cells in graft-versus-host disease (GVHD), we used allogeneic MHC class I and II disparate hematopoietic stem cell transplantation (allo-HSCT) models. We first analyzed the expression of ICOS by transferring CFSE-labeled donor T cells into irradiated allogeneic recipients and observed an increased expression of ICOS on alloreactive T cells compared to non-alloreactive T cells. We then studied B6-ICOS−/− alloreactive T cells and found intact proliferation in vivo (as determined by adoptive transfer of CFSE labeled T cells and donor T cell numbers in the spleen of allo-HSCT recipients), intact cytotoxicity, intact up regulation of activation markers, but decreased IFN-γ production in vitro. We then performed GVHD experiments in two models with full MHC class I and II disparity and observed significantly less GVHD morbidity and mortality in recipients of ICOS−/− donor T cells. Furthermore, histopathological analysis demonstrated less GVHD in all target organs (skin, liver, small bowel and large bowel) of recipients of ICOS−/− splenic T cells compared to recipients of wild type T cells. We harvested target organs (spleen, thymus, liver and gut) on days 7, 14, and 21 to examine donor T cell content (naïve and activated T cells) and found no significant difference in the total T cell numbers and subpopulations. Interestingly, in GVHD/graft-versus-tumor (GVT) experiments, ICOS−/− donor T cells displayed intact GVT activity, while their GVH activity was diminished. We then tested the levels of IFN-γ in the sera of mice undergoing GVHD and observed decreased serum levels in recipients of B6-ICOS−/− T cells. In conclusion, alloreactive ICOS−/− donor T cells display less GVHD morbidity and mortality due to decreased IFN-γ production, while proliferation, infiltration and GVT activity remain intact. These data suggests that strategies to inhibit ICOS could be useful for the prevention and/or treatment of GVHD in recipients of an allo-HSCT.

Donor BM Dendritic Cells Expressing IDO Limit Graft-Versus-Host Disease After Allogeneic Bone Marrow Transplant.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1331-1331
Author(s):  
Ying Lu ◽  
Wayne Harris ◽  
Jian-Ming Li ◽  
Edmund K. Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Marrow Transplant ◽  
Allogeneic Bone ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Th1 Polarization

Abstract Abstract 1331 Poster Board I-353 Background In contrast to the essential role of host dendritic cells (DC) in the initiation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactions, less is known about the effects of donor DC on T cells in these processes. We have previously reported that adding donor BM plasmacytoid DC (pDC) progenitors to a murine graft composed of purified hematopoietic stem cells (HSC) and T-cells increased donor activation and Th1 polarization leading to enhanced GVL activity without increasing GVHD (Li et al. 2007 Blood 110:2181), while larger numbers of human donor pDC were associated with less GVL activity following allogeneic bone marrow transplant (BMT) (Waller et al. 2001 Blood 97:2948). To explore the dissociation of GVHD from GVL we tested the hypothesis that activation of donor T-cells by donor pDC leads to reciprocal induction of indoleamine 2,3-dioxygenase (IDO) expression and immune counter-regulatory activity by donor DC that limits donor T-cell allo-reactivity. Methods pDC precursors were purified by high-speed FACS from un-stimulated BM harvested from wild type (WT) and IDO knock-out (IKO) mice. T-cell proliferation and immune polarization in response to indirect antigen presentation by syngenic DC was measured in mixed lymphocyte reaction (MLR) and by recovery of CFSE-labeled donor T-cells from allogeneic transplant recipients. IDO expression in DC was measured by FACS and intracellular staining using pDC from IKO BM as a negative staining control. FACS-purified 5 × 104 pDC either from WT mice or from IKO mice in combination with 3 × 103 c-kit+ Sca-1+ hematopoietic stem cells (HSC) and 3 × 105 T-cells were transplanted in MHC mismatched C57BL/6→B10.BR model following lethal irradiation. Results FACS-purified lineage−CD11cloCD11b− pDC expressed B220 (72%), CD90 (51%), and CD317 (PDCA-1) (93%), had low levels of MHC-II, partial expression of CD4, and lacked expression of CD24, CD80, CD86 and NK cell or granulocytic markers. IDO expression in purified pDC was up regulated by IFN-γ produced by syngenic T-cells in vitro in one-way MLR. In vivo proliferation of CFSE-labeled donor T-cells was enhanced in mice that received pDC from either WT or IKO mice. Co-transplantation of IKO pDC led to higher proliferation rates of CD8+ T-cells but not CD4+ T-cells compared with the proliferation of corresponding donor T-cell subset co-transplanted with WT DC. The incidence and severity of GVHD (weight loss and GVHD score) were markedly increased in recipients receiving pDC from IKO mice as compared with mice receiving WT pDC. The enhanced GVL activity of donor T-cells induced by transplanted donor WT pDC was abolished when IKO pDC were transplanted into tumor-bearing recipients. Transplanting WT donor pDC led to larger numbers of donor-derived CD4+CD25+Foxp3+ T-reg cells in the spleens of transplant recipients compared with mice receiving IKO pDC (p<0.01) in combination with purified HSC and T-cells. Conclusions Taken together, our data suggest IDO expression in pDC as a critical downstream event that inhibits continued T-cell activation and GVHD. We propose a feedback model in which donor pDC initially induce Th1 polarization of activated donor CD8+ T-cells that secret high levels of IFN-γ. IDO expressed by donor pDC in response to local IFN-γ subsequently induces a counter-regulatory effect including the generation of T-reg and down-modulation of CD8+ T-cell allo-reactivity and proliferation, limiting GVHD while preserving the GVL activity of donor T-cells. Disclosures No relevant conflicts of interest to declare.

Inhibition of Histone Methylation Arrests Ongoing Graft-Versus-Host Diseases in Mice by Selectively Inducing Apoptosis of Alloreactive Effector T Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 820-820
Author(s):  
Shan He ◽  
Jina Wang ◽  
Koji Kato ◽  
Fang Xie ◽  
Sooryanarayana Varambally ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Histone Methylation ◽  
Effector T Cells ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Novel Approaches ◽  
In Vivo Administration

Abstract Abstract 820 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with hematological malignancies. However, its success is limited by life-threatening graft-versus-host disease (GVHD). Novel approaches are needed to control GVHD. Recent studies have shown the importance of histone methylation in regulating the expression of genes associated with effector T cell differentiation and proliferation. Using several mouse models of allo-HSCT, we report that in vivo administration of the histone methylation inhibitor 3-Deazaneplanocin A (DZNep) arrested ongoing GVHD while preserving graft-versus-leukemia activity (GVL). To assess the therapeutic effect of pharmacologic modulation of histone methylation on GVHD, we administered DZNep to BALB/c mice receiving major histocompatibility-mismatched C57BL/6 mouse T cells 7 days after transplantation, in which GVHD had been fully established. Notably, injection of 12 doses of DZNep controlled the disease in these recipients, with approximately 80% of them surviving long-term without significant clinical signs of GVHD. We found that in vivo administration of DZNep caused selective apoptosis in alloantigen-activated T cells, but did not impair the generation of effector T cells that produced inflammatory cytokines (e.g., TNF-α, IFN-γ and IL-17) and cytotoxic molecules (e.g., granzyme B and Fas ligand). As a result, alloreactive T cells retained potent GVL activity, leading to improved overall survival of the recipients challenged by leukemic cells. These data suggest that DZNep-mediated inhibition of GVHD may be accounted for by reduced number of alloreactive effector T cells. In vitro culture assays showed that DZNep treatment induced apoptosis in T cells activated by anti-CD3/CD28 antibodies but not in naive T cells stimulated by IL-2 or IL-7. This effect was associated with DZNep's ability to selectively reduce trimethylation of histone H3 lysine 27 (H3K27), deplete the histone methyltranferase Ezh2 that specifically catalyzes trimethylation of H3K27, and activate Ezh2-repressed pro-apoptotic gene Bim. Inactivation of Bim partially protected alloreactive T cells from DZNep-mediated apoptosis. Importantly, unlike DNA methylation inhibitors, inhibition of histone methylation by DZNep had no toxicities to hematopoietic cells or impairment on the reconstitution of hematopoiesis and thymopoiesis. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat established GVHD and other T cell-mediated inflammatory disorders in a broad context. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

2015 ◽  
Vol 112 (4) ◽  
pp. 1125-1130 ◽  
Author(s):  
Martin Vaeth ◽  
Carina A. Bäuerlein ◽  
Tobias Pusch ◽  
Janina Findeis ◽  
Martin Chopra ◽  
...  
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Treg Cells ◽  
Target Tissue ◽  
Activated T Cells ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Advanced Therapy ◽  
Donor T Cells ◽  
Life Threatening

Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3+ regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8+ T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

scholarly journals Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3285-3292 ◽  
Author(s):  
Vanessa M. Hubbard ◽  
Jeffrey M. Eng ◽  
Teresa Ramirez-Montagut ◽  
Kartono H. Tjoe ◽  
Stephanie J. Muriglan ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Interleukin 4 ◽  
Activated T Cells ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Inducible Costimulator ◽  
Donor T Cells

AbstractInducible costimulator (ICOS) is expressed on activated and memory T cells and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft versus host disease (GVHD) and determined that ICOS expression was up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft versus leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of interferon-γ (IFN-γ), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (Th2) differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.

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

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

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

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

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

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

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2829-2836 ◽  
Author(s):  
Claudia Stuehler ◽  
Stephan Mielke ◽  
Manik Chatterjee ◽  
Johannes Duell ◽  
Sarah Lurati ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
T Cell Immunity ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Cell Immunity ◽  
Selective Depletion ◽  
Disease Specific

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Current treatment of GVHD relies on immunosuppressive regimens, considerably increasing the incidence of opportunistic infections. As T cells mediate both GVHD as well as protection against viral infections and the malignant disease, strategies to selectively target host-reactive T cells without impairing pathogen- and disease-specific immunity are highly warranted. Activation of T cells is accompanied by increased expression of the chaperone heat shock protein of 90 kDa (Hsp90), which stabilizes several key signaling pathways crucial for T-cell activation. In this study, selective targeting of Hsp90 in activated T lymphocytes with pharmacologic inhibitors already applied successfully in anticancer therapy resulted in induction of apoptosis predominantly in activated cells. Moreover, if T cells were stimulated with allogeneic dendritic cells, alloreactive T cells were selectively eliminated. In contrast, third party reactions including antiviral T-cell immunity were quantitatively and functionally fully preserved. These data suggest that Hsp90 represents a novel target for selective depletion of alloreactive T cells, and provide the rationale for application of Hsp90 inhibitors as potential approach to selectively prevent and treat GVHD in hematopoietic stem cell transplantation recipients without impairing pathogen- and disease-specific T-cell immunity.

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 Cytokines and costimulation in acute graft-versus-host disease

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

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

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