CCR1 Is Required for Treg-Mediated Protection From Lethal Acute Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1337-1337
Author(s):  
Michael J Carlson ◽  
James M. Coghill ◽  
Michelle L. West ◽  
Angela Panoskaltsis-Mortari ◽  
Bruce R. Blazar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Chemokine Receptor ◽  
Lymphoid Tissues ◽  
Allogeneic Bone ◽  
Widespread Application ◽  
Host Disease ◽  
Graft Versus Host ◽  
Target Organs

Abstract Abstract 1337 Poster Board I-359 INTRODUCTION Graft-versus-host disease (GVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Despite advances in understanding the etiology of GVHD it remains a formidable obstacle to the widespread application of BMT. A number of studies have demonstrated that T regulatory (Treg) cells represent a potential therapy for GVHD as Tregs have been shown to inhibit GVHD while preserving the beneficial graft-versus-leukemia (GVL) effect. Numerous groups, including our own, have demonstrated the importance of T cell migration in the pathology of GVHD. Following conditioning, donor T cells migrate to secondary lymphoid tissues. Once activated in the lymphatics, T cells migrate to GVHD target organs including; the skin, liver, lung and the gastrointestinal (GI) tract in response to the local production of chemokines. Disruption of chemokine-chemokine receptor interactions has been demonstrated to affect the pathology of GVHD. Previously, we have shown that Tregs lacking the chemokine receptor CCR5, which binds CCL3, CCL4, and CCL5, do not protect animals from lethal GVHD as well as WT Tregs, due to their impaired migration to the liver and lung. Thus, a greater understanding of the function of chemokine receptors on Tregs is important in deciphering how Tregs function and whether targeting these cells to lymphoid tissue or GVHD target organs would be preferable for treating patients in clinical trials. METHODS We utilized a parent into F1 haploidentical model to assess the role of CCR1 in Treg-mediated protection from GVHD. Here we demonstrate Tregs lacking CCR1, another receptor for CCL3 and CCL5, were unable to protect animals against lethal acute GVHD. While 67% of B6D2 recipients given 1×106 WT Tregs supplemented with 5×106 WT T cells and 3×106 B6 T cell-depleted BM cells survived, only 15% of the recipients given CCR1−/− Tregs survived (p < 0.03; Fisher's exact test). B6D2 recipient mice given WT Tregs had significantly reduced clinical scores for GVHD compared to B6D2 recipients of CCR1−/− Tregs (p <0.05) with elevated GVHD scores starting on day 28 post-transplant. Histopathology revealed significantly worse pathology in the liver (p < 0.03) and colon (p < 0.05) of CCR1−/− Treg recipients vs. WT Treg recipients. In vitro analysis demonstrated that CCR1−/− Tregs were capable of suppressing T cell responses to allo-antigen equally as well as WT Tregs, and CCR1−/− Tregs attained a normal activation phenotype. Interestingly, preliminary experiments suggested that CCR1−/− Tregs migrated to and/or expanded in GVHD target organs to a similar extent as WT Tregs. CONCLUSIONS Treg expression of CCR1 is required for the inhibition of GVHD. Tregs lacking CCR1 led to significantly more tissue destruction in the liver and colon, two predominant sites of GVHD pathology. Of interest, the migration of CCR1−/− Tregs to GVHD target organs and secondary lymphoid tissues did not appear to be compromised suggesting that CCR1 may be required for the function of Tregsin vivo. Disclosures No relevant conflicts of interest to declare.

scholarly journals Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3300-3307 ◽  
Author(s):  
Christian A. Wysocki ◽  
Qi Jiang ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Karen P. McKinnon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Allogeneic Bone Marrow Transplantation ◽  
Lymphoid Tissues ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

AbstractCD4+CD25+ regulatory T cells (Tregs) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by Tregs expressing the lymphoid homing molecule l-selectin. Here, we demonstrate that Tregs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5-/- Tregs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) Tregs. CCR5-/- Tregs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of Tregs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5-/- Tregs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in Treg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of Tregs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation.

scholarly journals Remodeling specific immunity by use of MHC tetramers: demonstration in a graft-versus-host disease model

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2045-2051 ◽  
Author(s):  
Barry J. Kappel ◽  
Javier Pinilla-Ibarz ◽  
Adam A. Kochman ◽  
Jeffrey M. Eng ◽  
Vanessa M. Hubbard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Populations ◽  
Solid Organ ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Mhc Molecules

Major histocompatibility complex (MHC) molecules carrying selected peptides will bind specifically to their cognate T-cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen-specific T-cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T-cell populations, while leaving the remaining T-cell repertoire and immune response intact. In this report, we successfully demonstrate that a tetramer-based depletion of T cells can be achieved in a murine model of allogeneic bone marrow transplantation. Depletion of a specific alloreactive population of donor splenocytes (< 0.5% of CD8+ T cells) prior to transplantation significantly decreased morbidity and mortality from graft-versus-host disease. There was no early regrowth of the antigen-specific T cells in the recipient and in vivo T-cell proliferation was greatly reduced as well. Survival was increased more than 3-fold over controls, yet the inherent antitumor activity of the transplant was retained. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T-cell clones, which could result in novel therapies for certain autoimmune disorders, T-cell malignancies, and solid organ graft rejection.

Protection of the Intestinal Epithelium from Conditioning with R-spondin1 Ameliorates Graft-Versus-Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 66-66 ◽  
Author(s):  
Shuichiro Takashima ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Takeshi Oshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Large Bowel ◽  
Immune Reconstitution ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tract Damage

Abstract Damage to the gastrointestinal (GI) tract by pretransplant conditioning regimen plays a critical role in amplifying graft-versus-host disease (GVHD). Thus protection of the GI tract from conditioning may represent a novel approach to prevent GVHD. R-Spondin1 (R-Spo1) is a novel class of soluble activator for Wnt/□-catenin signaling, and has potent and specific proliferative effects on the intestinal crypt cells; injection of R-Spo1 protects mice from chemotherapy-induced intestinal mucositis. We therefore hypothesized that administration of R-Spo1 could modulate GVHD by reducing the GI tract damage and improve outcome of allogeneic bone marrow transplantation (BMT). Lethally irradiated B6D2F1 (H-2b/d) mice were injected with 5 × 106 BM and 2 × 106 T cells from MHC-mismatched B6 (H-2b) donors on day 0. Mice were intravenously injected with 200 μg of R-Spo1 or diluent from days −3 to −1 and +1 to +3 after BMT. In vivo labeling assay of mitotic cells with BrdU demonstrated that the proliferative index, as determined by the percentages of BrdU-positive cells among crypt epithelial cells, was significantly greater in the small intestine of R-Spo1 treated mice than controls 4 days after BMT (57% ± 3% vs 48% ± 1%, P<0.05). Analysis of the mesenteric lymph nodes and spleens on day +7 demonstrated significantly reduced expansion of donor T cells in R-Spo1 treated recipients in association with reduced serum levels of IFN-□ and TNF-□ on day +7 when compared to controls (Table). GVHD was severe in allogeneic controls, with 12.5% survival by day +40, whereas 62.5% of R-Spo1-treated animals survived this period (Table). Histopathologic examination of the small and large bowel and liver showed significantly reduced GVHD pathology in R-Spo1 treated animals than in controls (Table). A flowcytometric analysis of the spleen and thymus after BMT showed that administration of R-Spo1 did not impair donor cell engraftment and T and B cell immune reconstitution. We next evaluated the impact of R-Spo1 on graft-versus-leukemia (GVL) effects. BMT was performed similarly as above with the addition of 5 × 104 host-type P815 leukemia cells (H-2d). All recipients of T cell-depleted BM died from leukemia by day +20 after BMT, while no leukemia death was observed in R-Spo1 treated allogeneic animals. Overall, R-Spo1 treatment improved outcome of allogeneic BMT by reducing GVHD, while maintaining immune reconstitution and GVL effects. Thus, administration of R-Spo1 reduces the GI tract damage and suppresses donor T cell activation and systemic GVHD, supporting a hypothesis that the GI tract plays a major role in the amplification of systemic GVHD. Brief treatment with R-Spo1 may serve as an effective adjunct to clinical regimens of GVHD prophylaxis. Pathology Scores Group Survivals on day+40 (%) Small bowel Large bowel Liver INF □ (ng/ml) TNF □ (pg/ml) TCD: T cell-depleted BMT, +T: T cell-repleted BMT, ND: not detected Data are expressed as mean ± SD. *P<0.01 vs control, **P<0.05 vs control TCD diluent 100 2.4± 0.9 3.5± 1.0 0.3± 0.3 ND ND +T diluent 12.5 8.3± 2.7 7.3± 1.9 2.0± 0.8 6.0 ± 2.4 103.7 ± 9.9 +T R-Spo1 62.5* 3.4±1.9** 3.9± 0.3** 0.8± 0.7** 2.3 ± 1.5** 55.4 ± 6.6**

scholarly journals Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 749-755 ◽  
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Chen Liu ◽  
Dennis Keith Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Γδ T Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P &lt; .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

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.

Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 556-565 ◽  
Author(s):  
Natalie Hartmann ◽  
Joanna J. Messmann ◽  
Frank Leithäuser ◽  
Maxi Weiswange ◽  
Michael Kluge ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cell Function ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Functions ◽  
T Cell Function

Abstract Graft-versus-host disease (GVHD) induced by transplant-derived T cells represents a major complication after allogeneic bone marrow transplantation (BMT). However, these T cells support engraftment, early T-cell immunity, and mediate the graft-versus-tumor (GVT) effect. Cytotoxic effector functions by transplanted T cells are predominantly mediated by the perforin/granzyme and the CD95/CD95L system. APG101, a novel recombinant human fusion protein consisting of the extracellular domain of CD95 and the Fc domain of an IgG1 antibody inhibited CD95L-induced apoptosis without interfering with T-cell function in vitro and was therefore tested for its ability to prevent GVHD in murine BMT models across minor or major histocompatibility barriers. Starting APG101 treatment either 1 day before or 6 days after transplantation effectively reduced clinical GVHD and rescued survival between 60% and 100% if GVHD was CD95L mediated. APG101 did not interfere with the GVT effect, because P815 mastocytoma and most importantly primary Bcr-Abl–transformed B-cell leukemias were completely eradicated by the alloantigen-specific T cells. Phenotype and homing of alloantigen-specific T cells or their perforin/granzyme-mediated cytotoxicity and proliferative capacity were not affected by APG101 treatment suggesting that APG101 therapy might be useful in GVHD prophylaxis without impairing T-cell function and most importantly preserving GVT activity.

Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4350-4356 ◽  
Author(s):  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Jeffrey S. Rubin ◽  
Aykut Uren ◽  
Lisbeth A. Welniak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone ◽  
Cell Transfer ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Transfer

Abstract We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF), an epithelial tissue repair factor, can ameliorate graft-versus-host disease (GVHD) after intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation (BMT). To determine whether this effect was dependent on a KGF-mediated mechanism affecting repair of conditioning-induced epithelial cell injury, we studied GVHD in the absence of conditioning using BALB/c severe combined immune-deficient (SCID) recipients given C57BL/6 T cells. KGF (5 mg/kg per day, subcutaneously) given either before or after T-cell transfer enhanced body weights and extended survival. KGF-treated recipients had elevated serum levels of the Th2 cytokine interleukin 13 (IL-13) on day 6 after T-cell transfer concomitant with reduced levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon gamma (IFN-γ). A 3-day KGF pretreatment also depressed the secondary in vitro mixed lymphocyte response (MLR) of C57BL/6 splenocytes taken 7 days after in vivo alloimmunization with irradiated BALB/c spleen cells. To determine whether KGF would inhibit host-antidonor–mediated BM rejection, pan-T-cell–depleted BALB/c BM cells were infused into sublethally irradiated C57BL/6 mice and administered KGF either before or before and after BMT. Surprisingly, all KGF schedules tested actually resulted in enhanced alloengraftment. The presence of KGF receptor on donor antihost alloreactive T cells could not be detected by binding studies with radiolabeled KGF, reverse transcriptase–polymerase chain reaction, and Western blotting. Therefore, the mechanism of action of KGF on inhibiting T-cell–mediated immune effects may not be due to a direct effect of KGF on T cells. These studies demonstrate that KGF, by mechanisms independent of repair of conditioning-induced injury, has great potential as an anti-GVHD therapeutic agent with the added benefit of inhibiting the rejection of pan-T-cell–depleted donor BM allografts.

In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2649-2656 ◽  
Author(s):  
Vu H. Nguyen ◽  
Robert Zeiser ◽  
Daniel L. daSilva ◽  
Daisy S. Chang ◽  
Andreas Beilhack ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Lymphoid Organs ◽  
Allogeneic Bone ◽  
Major Barrier ◽  
Peripheral Tissues ◽  
Host Disease ◽  
Graft Versus Host

Abstract CD4+CD25+ regulatory T cells (Tregs) suppress immune responses to alloantigens. The in vivo circulation and tissue localization of Tregs during an adaptive immune response remain unclear. We noninvasively tracked luciferase-expressing Tregs over time in an allogeneic bone marrow transplant model and demonstrated colocalization with effector T cells and initial expansion in secondary lymphoid organs before migration into inflamed tissues. Inflammation induced by irradiation and the allogeneic setting provided crucial stimuli for early Treg expansion and migration, leading to parallel reduction of effector T-cell proliferation in lymphoid organs and peripheral tissues. Treg transplants conferred long-term protection from systemic inflammatory challenge consistent with Treg in vivo survival. Suppression occurred during multiple phases of inflammation, but is optimal in the initial phase, providing protection from graft-versus-host disease while maintaining the graft-versus-tumor effect even at physiologic doses of Tregs due to their in vivo expansion, hence overcoming a major barrier to potential clinical applications of Tregs given their rarity.

scholarly journals Blockade of Interleukin 27 Signaling Attenuates Graft Versus Host Disease By Augmenting CD4+ and CD8+ Regulatory T Cell Reconstitution

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 150-150
Author(s):  
Ludovic Belle ◽  
Kimberle A. Agle ◽  
Vivian Zhou ◽  
Vanessa Yuan ◽  
Jie Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Regulatory T Cell ◽  
Wild Type ◽  
Host Disease ◽  
Graft Versus Host ◽  
Target Organs ◽  
Ifn Γ

Abstract The interleukin-6 (IL-6) cytokine superfamily (i.e. IL-6, IL-12, and IL-23) plays a major role in the modulation of inflammatory and regulatory pathways during graft versus host disease (GVHD). IL-27, a recently discovered member of this family, is a heterodimeric cytokine that is composed of the p28 and EBI3 subunits and signals through a heterodimeric receptor composed of WSX-1 and gp130. Notably, IL-6 also uses gp130 as a signaling component which biologically links IL-27 and IL-6. IL-27 has been shown to have opposing proinflammatory and immunoregulatory effects, but its role in GVHD is not well understood. To define the functional significance of IL-27, lethally irradiated Balb/c (H-2d) mice were transplanted with C57BL/6J (H-2b) BM and spleen cells, and then treated with an anti-IL-27p28-specific antibody on days 0 and +6. p28 antibody-treated animals had significantly improved weight recovery and overall survival (47% versus 0% survival at day 60, p=0.002), as well as reduced numbers of proinflammatory CD4+ and CD8+ IFN-γ+ T cells in GVHD target organs, when compared to isotype control antibody-treated mice. A similar outcome was observed in an MHC-matched, minor antigen disparate model (B6→Balb.B), indicating that this was not a strain-specific phenomenon. Given the similarities between IL-6 and IL-27, we examined whether blockade of IL-27 promoted regulatory T cell (Treg) reconstitution as has been observed with inhibition of IL-6 signaling. Recipients transplanted with BM grafts from B6 Foxp3EGFP reporter animals and treated with p28 antibody had a significant increase in the number of CD4+ nTregs, CD4+ iTregs and CD8+ iTregs in GVHD target organs, indicating that blockade of IL-27 augmented global Treg reconstitution. In fact, inhibition of IL-27 was more effective at augmenting Treg reconstitution than comparable antibody blockade of IL-6. To further elucidate the role of IL-27, we employed transgenic IL-27−/− and IL-27R−/− animals to dissect the relevant contributions of donor and recipient populations. Paradoxically, we observed that transplantation with IL-27−/− donor grafts exacerbated GVHD mortality and augmented accumulation of proinflammatory T cells, whereas transplantation of recipient IL-27−/− mice with wild type grafts had no effect on transplant outcomes. This discordance between antibody-based and genetic studies was unexpected and led us to consider whether there were steady state alterations in T cells from IL-27−/− animals that biased these cells towards a proinflammatory phenotype. To that end, we observed that naive CD8+ T cells from IL-27−/− mice had greater IFN-γ production than wild type cells after in vitro polyclonal stimulation and CD4+ nTregs from these animals had diminished expression of CXCR3 which is critical for Treg trafficking into inflamed tissue sites. Thus, the lack of endogenous IL-27 resulted in intrinsic immune dysregulation which led to an exacerbation of GVHD after transfer of these T cells into recipients. To resolve this paradox, we employed IL-27R−/− (WSX-1−/−) mice and demonstrated that mice transplanted with IL-27R−/− grafts had enhanced weight recovery and survival providing confirmation that blockade of IL-27 signaling reduced GVHD. In addition, using IL-27R−/− Foxp3EGFP reporter mice, we observed increased frequencies and numbers of CD4+ and CD8+ Foxp3+ T cells in mice reconstituted with IL-27R−/− grafts, confirming results observed with p28 antibody blockade. Since IL-10 is a mechanism by which CD4+ Tregs suppress GVHD and IL-27 has been shown to enhance T cell-derived IL-10 secretion in nontransplant models, we examined whether IL-27 blockade adversely affected IL-10 production by Tregs. Recipients transplanted with marrow grafts from IL-10.BitFoxp3EGFP dual reporter animals and treated with p28 antibody had a significant reduction in the frequency of IL-10-producing conventional CD4+ and CD8+ T cells in GVHD target organs. Notably, however, there was no difference in the frequency of CD4+ Foxp3+ IL-10+ T cells, indicating that blockade of IL-27 signaling preferentially affected conventional T cells and had no adverse effect on CD4+ Foxp3+ T cell-derived IL-10 production. In summary, these studies demonstrate that blockade of IL-27 signaling potently augments Treg reconstitution leading to a reduction in the severity of GVHD and may therefore represent a novel strategy to reduce mortality from this disease in man. Disclosures No relevant conflicts of interest to declare.

scholarly journals Absence of donor T-cell–derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 783-786 ◽  
Author(s):  
Chiara Borsotti ◽  
Anna R. K. Franklin ◽  
Sydney X. Lu ◽  
Theo D. Kim ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Donor T Cells ◽  
Membrane Bound

Abstract Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-α converting enzyme (TACE). To study the contribution of donor T-cell–derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNFΔ/Δ) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.

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