IDO and Regulatory T Cell Support Are Critical for Cytotoxic T Lymphocyte-Associated Ag-4 Ig-Mediated Long-Term Solid Organ Allograft Survival

Sucher, Robert; Fischler, Klaus; Oberhuber, Rupert; Kronberger, Irmgard; Margreiter, Christian; Öllinger, Robert; Schneeberger, Stefan; Fuchs, Dietmar; Werner, Ernst R.; Watschinger, Katrin; Zelger, Bettina; Tellides, George; Pilat, Nina; Pratschke, Johann; Margreiter, Raimund; Wekerle, Thomas; Brandacher, Gerald

doi:10.4049/jimmunol.1002777

Cited by 73 publications

(63 citation statements)

References 50 publications

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“…In contrast, the later phase comprises ASC that have undergone extensive class switching and affinity maturation within the GC, and the antibodies they produce are likely to be of higher affinity. In allograft transplantation, effective inhibition of T cell responses results in virtually no alloantibody production[40] (Fig 5) suggesting that post-GC ASCs are the dominant source of alloantibodies, and inhibiting the GC reaction may be an effective way to control graft-specific B cell responses. Indeed, by tracking alloreactive B cells, we were able to demonstrate the ability of CTLA4-Ig administered even as late as day 14 post-immunization to collapse established GC responses and significantly reduce the total numbers of H-2K d -specific B cells.…”

Section: Discussionmentioning

confidence: 99%

Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Young

Chen

Miller

et al. 2016

American Journal of Transplantation

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Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein CTLA4-Ig blocks T-cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective on naïve T cells and less so on activated or memory T cells. In this study, we used a mouse model of allo-sensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days post-sensitization, at inhibiting ongoing allo-specific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allo-specific germinal center (GC) B cell response and inhibited alloantibody production. Using adoptively transferred TCR-transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4+ and T follicular helper (Tfh) responses. Remarkably, delaying CTLA4-Ig until day 6 post-transplantation in a fully-mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, while transferred hyperimmune sera reversed the effects delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig at inhibiting ongoing B cell responses even when the graft-specific T cell response has been robustly established.

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Section: Discussionmentioning

confidence: 99%

Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Young

Chen

Miller

et al. 2016

American Journal of Transplantation

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“…Also T cell proliferation depends on Trp availability, thus IDO activation is a metabolic checkpoint of immunoregulation [92] . IDO activity is crucially involved in the control of T cell proliferation and in the generation of regulatory T cells, and thus in the suppression of autoimmune responses and promotion of tolerance [92,93] . …”

Section: Tryptophan Breakdownmentioning

confidence: 99%

Antioxidants, inflammation and cardiovascular disease

Mangge

Becker

Fuchs

et al. 2014

WJC

293

159

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Multiple factors are involved in the etiology of cardiovascular disease (CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells, leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species (ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or, and even more likely, due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress, however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover, molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signaling pathways involved in the regulation of immunological, metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response, interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, fibroblasts, endothelial and epithelial cells. Neopterin, a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase (NOS) is induced in several cell types to generate nitric oxide (NO). NO, despite its low reactivity, is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin (BH4), which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite (ONOO -) is formed solely in the presence of superoxide anion (O2 -). Neopterin and kynurenine to tryptophan ratio (Kyn/Trp), as an estimate of IDO enzyme activity, are robust markers of immune activation in vitro and in vivo . Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise, a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C, -E and -B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites, BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD. REVIEWSubmit a

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“…Short-course treatment with CTLA4Ig at the time of transplant (termed 'CTLA4Ig induction'), commonly used in previous models (34,35), prolonged graft survival compared to untreated mice (p=0.015; syngeneic grafts were accepted long-term) (Figure 1a).…”

Section: Ctla4ig Prolongs Heart Graft Survival In a Dose-dependent Mamentioning

confidence: 99%

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

Schwarz

Unger

Mahr

et al. 2016

American Journal of Transplantation

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B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

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IDO and Regulatory T Cell Support Are Critical for Cytotoxic T Lymphocyte-Associated Ag-4 Ig-Mediated Long-Term Solid Organ Allograft Survival

Cited by 73 publications

References 50 publications

Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Antioxidants, inflammation and cardiovascular disease

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

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