scholarly journals Anti-IL-12/23 p40 Antibody Attenuates Chronic Graft Versus Host Disease Via Suppression of IFN-γ/IL-17-Producing Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1095-1095
Author(s):  
Taiga Kuroi ◽  
Sachiyo Okamoto ◽  
Kyosuke Saeki ◽  
Yujin Kobayashi ◽  
Hisakazu Nishimori ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Th17 Cells ◽  
Chronic Gvhd ◽  
Th2 Cells ◽  
Double Positive ◽  
Host Disease ◽  
Graft Versus Host ◽  
Single Positive ◽  
Ifn Γ

Abstract Chronic graft-versus-host disease (GVHD) remains a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells as well as in inducing IFN-γ/IL-17 double-producing cells. Because monoclonal antibody (mAb) targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12 and IL-23 receptor-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model: B10.D2 (H-2d)→Balb/c (H-2d). Sublethally irradiated BALB/c mice were transplanted with 2×106 spleen T cells and 8×106 TCD-BM cells from B10.D2 mice. Full donor chimerism was recognized. Anti-p40 mAb was injected peritoneally on every third day from day 0 of BMT. We found that anti-p40 mAb significantly ameliorated the clinical score compared with the controls (P < 0.05). Histopathological examination of the skin on day 28 showed significantly reduced chronic GVHD damage in anti-p40 mAb-treated animals (2.8 ± 0.4 vs. 6.0± 0.3, P < 0.01). Anti-p40 mAb was injected intraperitoneally to mice from day 15 of BMT, when mice had just developed clinical signs of chronic GVHD, and anti-p40 mAb significantly improved the clinical scores (P < 0.05). Cells isolated from PLNs were harvested on day 28 after BMT and analyzed for cytokine expression. Intracellular staining revealed that IFN γ single positive (IL-17-) and IFN γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients (38±9% vs. 58±8%, P=0.1) (1.5±0.2% vs. 4.0±0.4%, P=0.0003). The cytokine levels of IFN γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients (IFN γ; 10.0±0.6 pg/ml vs. 35±7 pg/ml, P=0.03, IL-17; 2.8 pg/ml vs. 7.5±2 pg/ml, P=0.2). Since IFN γ/IL-17 double-positive cells are enriched in the target organs of several autoimmune disease models, it has been suggested that these double producers are particularly pathogenic in tissue inflammation and autoimmunity. These double-positive cells show higher expression of T-bet and lower expression of ROR γt than IL-17 single-positive T cells. Therefore, we examined ROR γt and T-bet expression in donor IL-17+ CD4+ T cells isolated from PLNs harvested on day 28 after BMT. Anti-p40 mAb-treated recipients displayed marginally higher ROR γt expression than control-treated allogeneic recipients (4.7±0.6% vs. 3.2±0.5%, P = 0.08). By contrast, anti-p40 mAb-treated recipients showed significantly lower T-bet expression than controls (0.77±0.2% vs. 1.6±0.3%, P = 0.03). This reduction in T-bet expression was associated with IL-22 production by T cell from anti-p40 mAb-treated recipients (42±18 pg/ml vs. 110±17 pg/ml, P = 0.03). The levels of IL-22 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients 28 days after BMT (19±5 pg/ml vs. 206±78 pg/ml, P = 0.04). These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells. Moduration of the IL-12/IL-23 pathway may represent a new strategy for the treatment of chronic GVHD and anti-p40 which is clinically available as ustekinumab, might be promising therapeutic agents for chronic GVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3804-3813 ◽  
Author(s):  
Xiao Chen ◽  
Sanja Vodanovic-Jankovic ◽  
Bryon Johnson ◽  
Melissa Keller ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHD-associated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4+CD25+Foxp3+ regulatory T cells during the course of acute GVHD. This leads to the expansion of donor-derived CD4+ T cells with TH1 and TH17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4+CD25+ regulatory T cells coupled with unregulated TH1 and TH17 cells leads to the development of autoimmunity and that donor-derived TH1 and TH17 cells serve as the nexus between acute and chronic GVHD.

Interleukin-2-Producing CD4+OX40+ T Cell as a Target for the Treatment of Chronic Graft-Versus-Host-Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1816-1816
Author(s):  
Takero Shindo ◽  
Takayuki Ishikawa ◽  
Akiko Fukunaga ◽  
Toshiyuki Hori ◽  
Takashi Uchiyama
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
Host Disease ◽  
Effector Cells ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract Chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious complication, for which limited therapeutic approaches exist. Thymus-derived autoreactive as well as alloreactive T cells are shown to be involved in the development of chronic GVHD and CD4+ T cells are regarded to play a central role. OX40 (CD134) is known to play an important role in co-stimulation and survival elongation of CD4+ T cells, and murine models revealed that the interaction of OX40/OX40-ligand constitutes an essential parts in autoimmune and alloimmune responses. Since we showed that the increase of CD4+OX40+ T cells in peripheral blood of allo-HSCT recipients precedes the occurrence of chronic GVHD (Kotani A et al. Blood2001; 98: 3162–4), we have paid attention to the role of peripheral blood CD4+OX40+ T cells in the development of chronic GVHD. To further know the characteristics of peripheral blood CD4+OX40+ T cells from patients after allo-HSCT, we analyzed surface phenotype and the ability of cytokine production of CD4+ T cells from 25 allo-HSCT recipients. A majority of CD4+OX40+ T cells showed CD45RO+CD62L+CCR7+, while CD4+OX40− T cells were mainly CD45RO+CD62L−CCR7−. When stimulated with PMA and ionomycin, a significant part of CD4+OX40+ T cells produced interleukin-2 (IL-2). In contrast, a majority of CD4+OX40−HLA-DR+ T cells, the ratio of which also increased in peripheral blood of allo-HSCT recipients, produced interferon-γ (IFN-γ). Thus, the pattern of the expression of activation antigens on CD4+ T cells is a landmark of the potential to produce IL-2 or IFN-γ. When clinical data were combined, patients suffering from chronic GVHD showed increased ratio of IL-2-producing CD4+OX40+ T cells among CD4+ T cells (more than 10%). In fact, it correlates more closely (p=0.016) to the occurrence of chronic GVHD than the ratio of CD4+OX40+ T cells or that of IL-2-producing CD4+ T cells (p=0.06). Interestingly, the ratio of IFN-γ-producing CD4+ T cells does not correlate (p=0.95), suggesting that they do not contribute to the process of ongoing chronic GVHD. As CD4+OX40+ T cells share the characteristics of central memory T cells, we hypothesized that CD4+OX40+ T cells, which home secondary lymphoid organs, are stimulated with antigens and develop into effector cells, some of which induce chronic GVHD. Then we collected CD4+ T cells from recipients of allo-HSCT and sorted them into OX40+ and OX40− fractions. When sorted cells were stimulated with immobilized anti-CD3 and soluble anti-CD28 (CD3/28 stimulation), IL-2-producing cells were detected mainly in OX40+ fraction and IFN-γ-producing cells were abundantly and exclusively observed in OX40− fraction. When sorted cells were stimulated with CD3/28 for 48 hr, followed by 4-day cultivation with IL-2, OX40+ cells showed vigorous growth without reducing viability. In addition, re-stimulation with CD3/CD28 revealed that OX40+ cells produce a large amount of IFN-γ or IL-4. In this way, peripheral blood CD4+OX40+ T cells have potential to easily differenciate into effector cells, which may contribute to the development of chronic GVHD. The signaling from OX40 may also accelerate this process. Targeted therapy against IL2-producing CD4+OX40+ T cells may afford a breakthrough in the treatment of chronic GVHD.

scholarly journals IL-17 contributes to CD4-mediated graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 945-952 ◽  
Author(s):  
Lucy W. Kappel ◽  
Gabrielle L. Goldberg ◽  
Christopher G. King ◽  
David Y. Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokines ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Interleukin 17 ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract CD4+ interleukin-17 (IL-17)+ T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4+ donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17−/− T-cell recipients. However, upon transfer of murine IL-17−/− CD4+ T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4+ T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17−/− CD4+ T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-γ–secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-γ, IL-4, and IL-6) in recipients of IL-17−/− CD4+ T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.

scholarly journals Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 3101-3112 ◽  
Author(s):  
Tangsheng Yi ◽  
Ying Chen ◽  
Lin Wang ◽  
Gong Du ◽  
Daniel Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Tissue Damage ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Tissue Specific ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Th17 Differentiation

In acute graft-versus-host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-γ (IFN-γ) in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-γ–inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.

scholarly journals Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2101-2110 ◽  
Author(s):  
Tangsheng Yi ◽  
Dongchang Zhao ◽  
Chia-Lei Lin ◽  
Chunyan Zhang ◽  
Ying Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Graft Versus Host Disease ◽  
Proinflammatory Cytokine ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Th17 is a newly identified T-cell lineage that secretes proinflammatory cytokine IL-17. Th17 cells have been shown to play a critical role in mediating autoimmune diseases such as EAE, colitis, and arthritis, but their role in the pathogenesis of graft-versus-host disease (GVHD) is still unknown. Here we showed that, in an acute GVHD model of C57BL/6 (H-2b) donor to BALB/c (H-2d) recipient, IL-17−/− donor T cells manifested an augmented Th1 differentiation and IFN-γ production and induced exacerbated acute GVHD. Severe tissue damage mediated by IL-17−/− donor T cells was associated with increased Th1 infiltration, up-regulation of chemokine receptors by donor T cells, and enhanced tissue expression of inflammatory chemokines. Administration of recombinant IL-17 and neutralizing IFN-γ in the recipients given IL-17−/− donor cells ameliorated the acute GVHD. Furthermore, the regulation of Th1 differentiation by IL-17 or Th17 may be through its influence on host DCs. Our results indicate that donor Th17 cells can down-regulate Th1 differentiation and ameliorate acute GVHD in allogeneic recipients, and that treatments neutralizing proinflammatory cytokine IL-17 may augment acute GVHD as well as other inflammatory autoimmune diseases.

scholarly journals IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qingxiao Song ◽  
Xiaoning Wang ◽  
Xiwei Wu ◽  
Tae Hyuk Kang ◽  
Hanjun Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Mononuclear Phagocyte ◽  
Mononuclear Phagocytes ◽  
Dependent Manner ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Potential Efficacy ◽  
Ifn Γ

AbstractEfforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17−IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.

scholarly journals Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1756-1764 ◽  
Author(s):  
Yukimi Sakoda ◽  
Daigo Hashimoto ◽  
Shoji Asakura ◽  
Kengo Takeuchi ◽  
Mine Harada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

scholarly journals IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host Disease

2014 ◽  
Vol 20 (2) ◽  
pp. 192-201 ◽  
Author(s):  
Elizabeth O. Stenger ◽  
Brian R. Rosborough ◽  
Lisa R. Mathews ◽  
Huihui Ma ◽  
Markus Y. Mapara ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

scholarly journals Interleukin-12 Preserves the Graft-Versus-Leukemia Effect of Allogeneic CD8 T Cells While Inhibiting CD4-Dependent Graft-Versus-Host Disease in Mice

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4651-4660 ◽  
Author(s):  
Yong-Guang Yang ◽  
Justin J. Sergio ◽  
Denise A. Pearson ◽  
Gregory L. Szot ◽  
Akira Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Effect ◽  
Graft Versus Host Disease ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
Spleen Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Ifn Γ

We have recently demonstrated that a single injection of 4,900 IU of interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex plus minor antigen-mismatched BMT model (A/J → B10, H-2a → H-2b), in which donor CD4+ T cells are required for the induction of acute GVHD. We show here that donor CD8-dependent graft-versus-leukemia (GVL) effects against EL4 (H-2b) leukemia/lymphoma can be preserved while GVHD is inhibited by IL-12 in this model. In mice in which IL-12 mediated a significant protective effect against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated alloreactivity, protection was not observed in recipients of either syngeneic (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analyzed IL-12–treated recipients of EL4 and A/J spleen cells which survived for more than 100 days. No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or histologic examination. Both GVL effects and the inhibitory effect of IL-12 on GVHD were diminished by neutralizing anti–interferon-γ (IFN-γ) monoclonal antibody. This study demonstrates that IL-12–induced IFN-γ production plays a role in the protective effect of IL-12 against GVHD. Furthermore, IFN-γ is involved in the GVL effect against EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single cytokine, IFN-γ. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreactivity.

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.

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