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 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 Expression of the T-Cell Activation Antigen, OX-40, Identifies Alloreactive T Cells in Acute Graft-Versus-Host Disease

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4652-4658 ◽  
Author(s):  
Thomas V. Tittle ◽  
Andrew D. Weinberg ◽  
Cara N. Steinkeler ◽  
Richard T. Maziarz
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Peripheral Blood Lymphocytes ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract The OX-40 molecule is expressed on the surface of recently activated T lymphocytes. The presence of OX-40 on CD4+ T cells was analyzed in a rat haplo-identical (parental → F1) bone marrow transplant model of acute graft-versus-host disease (aGVHD). Increased numbers of activated CD4+ T cells that expressed the OX-40 antigen were detected in peripheral blood soon after transplantation before the earliest sign of disease. The peak of OX-40 expression occurred 12 days posttransplantation with a range of 18% to 36% of circulating T cells and remained 10-fold above background, never returning to baseline. A slight increase in OX-40 expression (range, 1% to 6%) was also detected on peripheral blood lymphocytes from control syngeneic F1 → F1 recipients. OX-40+ T cells were isolated from spleen, skin, lymph node, and liver tissue of rats undergoing aGVHD, but not in syngeneic transplants. OX-40+ T cells isolated from these tissues were of donor origin and were shown to be allo-reactive. These data raise the possibility of using the OX-40 antibody to detect and deplete selectively the T cells that cause aGVHD.

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 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.

Donor CD4+ T Cells That Possess Both Allo- and Autoreactivity in Transplants Mediate Chronic Graft Versus Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3555-3555
Author(s):  
Dongchang Zhao ◽  
Yu-Hong Chen ◽  
James Young ◽  
Elizabeth Shen ◽  
Tangsheng Yi ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Spleen Cells ◽  
Autoreactive T Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 3555 Poster Board III-492 Chronic graft versus host disease (GVHD) is considered an autoimmune-like disease mediated by donor CD4+ T cells, but the role and origin of the autoreactive T cells remain controversial. Here, we report that, in a chronic GVHD model of MHC-matched DBA/2 (H-2d) donor to BALB/c (H-2d) host, donor spleen cells induced autoimmune-like chronic GVHD in thymectomized allogeneic BALB/c but not in syngeneic DBA/2 recipients. The spleen cells from the former but not the latter recipients induced autoimmune-like disease in the secondary DBA/2 recipients, indicating that autoreactive donor CD4+ T cells from transplants are expanded and contribute to chronic GVHD pathogenesis. In addition, we found that both auto- and alloreactive donor CD4+ T cells generated from primary chronic GVHD recipients via serial in vivo and in vitro expansion proliferated to donor and host DC stimulation and both induced autoimmune-like disease in syngeneic and allogeneic recipients. Furthermore, the clonal expansion and TCR spreading of the autoreactive T cells in chronic GVHD recipients were following the alloreactive T cells, as revealed by TCR-spectrum typing and skewing of TCR-CDR3 length; No dual TCR was expressed by the donor-type T cells with both allo- and autoreactivity; and the autoreactive hybridoma T clones proliferated to stimulation by both syngeneic and allogeneic DCs. Taken together, these results demonstrate that donor CD4+ T cells that possess both allo- and autoreactivity in transplants are expanded in recipients and contribute to chronic GVHD pathogenesis, and the allo- and autoreactivity of the donor T cells can be mediated by a single TCR. Disclosures: No relevant conflicts of interest to declare.

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 Bone Marrow NK1.1− and NK1.1+ T Cells Reciprocally Regulate Acute Graft versus Host Disease

1999 ◽  
Vol 189 (7) ◽  
pp. 1073-1081 ◽  
Author(s):  
Defu Zeng ◽  
David Lewis ◽  
Sussan Dejbakhsh-Jones ◽  
Fengshuo Lan ◽  
Marcos García-Ojeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented &lt;1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of 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.

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