Publications by authors named "Simon Heidegger"

23 Publications

  • Page 1 of 1

Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy: A Case Report.

Neurol Neuroimmunol Neuroinflamm 2021 07 20;8(5). Epub 2021 Jul 20.

From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.

Objective: We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).

Results: A 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits.

Discussion: This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.
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http://dx.doi.org/10.1212/NXI.0000000000001042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293283PMC
July 2021

Tumor cell-intrinsic RIG-I signaling governs synergistic effects of immunogenic cancer therapies and checkpoint inhibitors in mice.

Eur J Immunol 2021 Jun 5;51(6):1531-1534. Epub 2021 Apr 5.

Department of Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.

Immunogenic cancer therapies, including radiation and hypomethylating agents, such as 5-azacytidine, rely on tumor cell-intrinsic activation of the RNA receptor RIG-I for their synergism with immune checkpoint inhibitors. Possible RIG-I ligands are small nuclear RNA (snRNA) and endogenous retroviral elements (ERV) leaking from the nucleus during programmed cell death.
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http://dx.doi.org/10.1002/eji.202049158DOI Listing
June 2021

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells.

Sci Rep 2019 10 18;9(1):14955. Epub 2019 Oct 18.

Department of Medicine III, Technical University of Munich (TUM), School of Medicine, Klinikum rechts der Isar TUM, Ismaninger Straße 22, 81675, Munich, Germany.

Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.
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http://dx.doi.org/10.1038/s41598-019-51431-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800427PMC
October 2019

RIG-I activation is critical for responsiveness to checkpoint blockade.

Sci Immunol 2019 09;4(39)

Department of Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.

Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti-CTLA-4 and its combination with anti-PD-1 rely on tumor cell-intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell-intrinsic RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103 dendritic cells, subsequent expansion of tumor antigen-specific CD8 T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5'- triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti-CTLA-4 checkpoint blockade, high RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer.
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http://dx.doi.org/10.1126/sciimmunol.aau8943DOI Listing
September 2019

Targeting intrinsic RIG-I signaling turns melanoma cells into type I interferon-releasing cellular antitumor vaccines.

Oncoimmunology 2019;8(4):e1570779. Epub 2019 Feb 11.

Medizinische Klinik und Poliklinik 3, Klinikum rechts der Isar, Technische Universität, Munich, Germany.

Resistance to cell death and evasion of immunosurveillance are major causes of cancer persistence and progression. Tumor cell-intrinsic activation of the RNA receptor retinoic acid-inducible gene-I (RIG-I) can trigger an immunogenic form of programmed tumor cell death, but its impact on antitumor responses remains largely unexplored. We show that activation of intrinsic RIG-I signaling induces melanoma cell death that enforces cross-presentation of tumor-associated antigens by bystander dendritic cells. This results in systemic expansion and activation of tumor-antigen specific T cells with subsequent regression of pre-established melanoma. These processes were dependent on the signaling hub MAVS and type I interferon (IFN-I) signaling in the host cell. Using melanoma cells deficient for the transcription factors IRF3 and IRF7, we demonstrate that RIG-I-activated tumor cells used as a vaccine are a relevant source of IFN-I during T cell cross-priming . Thus, our findings may facilitate translational development of personalized anticancer vaccines.
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http://dx.doi.org/10.1080/2162402X.2019.1570779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422402PMC
February 2019

RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade.

EBioMedicine 2019 Mar 6;41:146-155. Epub 2019 Mar 6.

Medizinische Klinik und Poliklinik III, Klinikum rechts der Isar, Technische Universität, Munich, Germany. Electronic address:

Background: Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches.

Methods: Here we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5'-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models.

Findings: We found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8 T cells that translates into potent antitumor immunity. RIG-I-induced cross-priming of cytotoxic T cells as well as antitumor immunity were dependent on the host adapter protein MAVS and type I interferon (IFN-I) signaling and were mediated by dendritic cells.

Interpretation: Overall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2019.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444128PMC
March 2019

Innate Immune Stimulation in Cancer Therapy.

Hematol Oncol Clin North Am 2019 04 9;33(2):215-231. Epub 2019 Jan 9.

Division of Clinical Pharmacology, Center of Integrated Protein Science Munich (CIPS-M), Klinikum der Universität München, Lindwurmstrasse 2a, Munich 80337, Germany. Electronic address:

The innate immune system has evolved as a first line of defense against invading pathogens and acts via classes of germline-encoded receptor systems to respond with proinflammatory cytokines. Innate immune cells, predominantly cells of the myeloid compartment, are capable of providing a potent basis for boosting adaptive immunity in malignant diseases. The authors review their current understanding of the molecular mechanisms whereby innate pattern recognition receptors participate in immunosurveillance of cancer cells. They discuss how innate effector mechanisms are currently being targeted pharmacologically and how improved understanding of the biology of these pathways is leading to novel immunotherapies of cancer.
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http://dx.doi.org/10.1016/j.hoc.2018.12.002DOI Listing
April 2019

Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling.

Int J Radiat Oncol Biol Phys 2019 03 29;103(4):970-976. Epub 2018 Nov 29.

Klinik und Poliklinik für Innere Medizin 3, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Purpose: Type I interferon (IFN-I) and interleukin (IL)-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress such as irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce the severity of acute GVHD after allo-HSCT with myeloablative TBI. However, the role of biologically related type III interferon (IFN-III), also known as interferon lambda (IFN-λ) or IL-28, in this context is unclear. We therefore studied the role of the IFN-III pathway in thymic regeneration and GVHD after TBI and allo-HSCT.

Methods And Materials: Cohoused wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor alpha subunit-deficient/IL-28Ra) mice were analyzed in models of TBI-induced thymus damage and a model of GVHD after allo-HSCT with myeloablative TBI. PASylated IFN-III (PASylated IL-28A, XL-protein GmbH) was generated to prolong the plasma half-life of IFN-III. Pharmacologic activity and the effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested.

Results: The course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28Ra mice was comparable to those in WT mice. Activation of the IFN-III pathway by PASylated IL-28A did not significantly modulate GVHD after allo-HSCT with TBI. Furthermore, IL28Ra mice and WT mice showed similar thymus regeneration after radiation, which could also not be significantly modulated by IFN-III receptor engagement using PASylated IL-28A.

Conclusions: We analyzed the role of IFN-III signaling during radiation-mediated acute tissue injury. Despite molecular and biologic homologies with IFN-I and IL-22, IFN-III signaling did not improve thymus regeneration after radiation or the course of GVHD after myeloablative TBI and allo-HSCT.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.038DOI Listing
March 2019

A20 Restrains Thymic Regulatory T Cell Development.

J Immunol 2017 10 25;199(7):2356-2365. Epub 2017 Aug 25.

Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technische Universität, 81675 Munich, Germany;

Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T) cells in the thymus. Activation of NF-κB transcription factors is critically required for T cell development, partly via initiating Foxp3 expression. NF-κB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4 T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T differentiation. A20-deficient thymic T cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T cells. Furthermore, we found that the increase in T cells in T cell-specific A20-deficient mice was already observed in CD4 single-positive CD25 GITR Foxp3 thymic T cell progenitors. T cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T cell development. A20-deficient T cells efficiently suppressed effector T cell-mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T cells in check, A20 thus integrates T cell activity and increased effector T cell survival into an efficient CD4 T cell response.
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http://dx.doi.org/10.4049/jimmunol.1602102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617121PMC
October 2017

RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.

Sci Transl Med 2017 04;9(386)

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.
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http://dx.doi.org/10.1126/scitranslmed.aag2513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604790PMC
April 2017

Cutting Edge in IFN Regulation: Inflammatory Caspases Cleave cGAS.

Immunity 2017 03;46(3):333-335

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. Electronic address:

Caspases have important functions beyond their established role in driving inflammation and apoptosis. In this issue of Immunity, Wang et al. (2017) demonstrate that inflammasome-triggered caspases cleave and inactivate the DNA sensor cGAS, thus restricting the type I interferon response to cytosolic DNA.
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http://dx.doi.org/10.1016/j.immuni.2017.03.004DOI Listing
March 2017

Card9 controls Dectin-1-induced T-cell cytotoxicity and tumor growth in mice.

Eur J Immunol 2017 05 10;47(5):872-879. Epub 2017 Apr 10.

Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität, Munich, Germany.

Activation of the C-type lectin receptor Dectin-1 by β-glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8 cytotoxic T-cell (CTL) responses without additional adjuvants, the Dectin-1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin-1-induced CTL cross-priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice. Thus, our results demonstrate that Dectin-1-triggered Card9 signaling but not inflammasome activation can potently cross-prime Ag-specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development.
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http://dx.doi.org/10.1002/eji.201646775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434796PMC
May 2017

Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery.

Nanoscale 2016 Jan;8(2):938-48

Center for Integrated Protein Science Munich (CIPSM), Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, 80336 Munich, Germany. and Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland.

Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.
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http://dx.doi.org/10.1039/c5nr06122aDOI Listing
January 2016

Mycoplasma hyorhinis-Contaminated Cell Lines Activate Primary Innate Immune Cells via a Protease-Sensitive Factor.

PLoS One 2015 13;10(11):e0142523. Epub 2015 Nov 13.

Center for Integrated Protein Science Munich (CIPSM), Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.

Mycoplasma are a frequent and occult contaminant of cell cultures, whereby these prokaryotic organisms can modify many aspects of cell physiology, rendering experiments that are conducted with such contaminated cells problematic. Chronic Mycoplasma contamination in human monocytic cells lines has been associated with suppressed Toll-like receptor (TLR) function. In contrast, we show here that components derived from a Mycoplasma hyorhinis-infected cell line can activate innate immunity in non-infected primary immune cells. Release of pro-inflammatory cytokines such as IL-6 by dendritic cells in response to Mycoplasma hyorhinis-infected cell components was critically dependent on the adapter protein MyD88 but only partially on TLR2. Unlike canonical TLR2 signaling that is triggered in response to the detection of Mycoplasma infection, innate immune activation by components of Mycoplasma-infected cells was inhibited by chloroquine treatment and sensitive to protease treatment. We further show that in plasmacytoid dendritic cells, soluble factors from Mycoplasma hyorhinis-infected cells induce the production of large amounts of IFN-α. We conclude that Mycoplasma hyorhinis-infected cell lines release protein factors that can potently activate co-cultured innate immune cells via a previously unrecognized mechanism, thus limiting the validity of such co-culture experiments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643973PMC
July 2016

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection.

J Immunol 2015 Nov 21;195(9):4387-95. Epub 2015 Sep 21.

Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland; Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and

Innate immune recognition of RNA is key for the initiation of immunity in response to viral infection. Although the factors controlling the detection of viral RNA by innate immune receptors in host cells are increasingly well understood, little is known about the dynamic changes in signaling after the initial triggering of these receptors. In this study, we report that preconditioning with the synthetic dsRNA polyinosinic-polycytidylic acid [poly(I:C)], a mimetic of viral RNA, rapidly reprograms murine APCs by simultaneously augmenting sensitivity of endosomal TLRs and inhibiting activation of RIG-I-like receptors (RLRs) in an IFN-β-dependent manner. These changes in receptor sensitivity were also seen in vivo after treatment of mice with poly(I:C). Mechanistically, the increased sensitivity of the TLR pathway was associated with elevated MAPK and NF-κB activity. The RLR response was inhibited downstream of TANK-binding kinase-1, resulting in decreased IFN regulatory factor 3 phosphorylation. Reprogramming of pattern-recognition receptor signaling also occurred after viral infection, because infection of host cells with Sendai virus or their exposure to supernatant from virus-infected cells induced the same changes in TLR and RLR sensitivity as poly(I:C). Thus, innate recognition of viral infection critically modifies responses to pattern-recognition receptor stimulation. These dynamic adaptations to infection may reinforce antiviral immunity and at the same time serve to limit pathological inflammation.
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http://dx.doi.org/10.4049/jimmunol.1500079DOI Listing
November 2015

The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation.

Front Immunol 2014 18;5:337. Epub 2014 Jul 18.

III. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München , Munich , Germany ; Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center , New York, NY , USA.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.
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http://dx.doi.org/10.3389/fimmu.2014.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102927PMC
August 2014

Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma.

Onco Targets Ther 2014 20;7:1123-7. Epub 2014 Jun 20.

III Medical Department, Technische Universität München, Munich, Germany.

Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.
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http://dx.doi.org/10.2147/OTT.S59795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074177PMC
July 2014

Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

Blood 2013 Oct 3;122(15):2591-9. Epub 2013 Jul 3.

Center for Integrated Protein Science Munich, Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany;

Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.
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http://dx.doi.org/10.1182/blood-2013-01-479311DOI Listing
October 2013

Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells.

J Thorac Oncol 2013 Aug;8(8):1032-42

Department of Internal Medicine IV, Division of Clinical Pharmacology and Center of Integrated Protein Science, Ludwig-Maximilians Universität München, Member of the German Center for Lung Research, Munich, Germany.

Introduction: In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients.

Methods: Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay.

Results: We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed.

Conclusion: IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype.
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http://dx.doi.org/10.1097/JTO.0b013e31829923c8DOI Listing
August 2013

TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice.

J Immunol 2013 May 15;190(10):5313-20. Epub 2013 Apr 15.

Center for Integrated Protein Science Munich, Klinische Pharmakologie, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.

The trafficking of effector T cells is tightly regulated by the expression of site-specific sets of homing molecules. In contrast, naive T cells are generally assumed to express a uniform pattern of homing molecules and to follow a random distribution within the blood and secondary lymphoid organs. In this study, we demonstrate that systemic infection fundamentally modifies the trafficking of circulating naive CD8(+) T cells. We show that on naive CD8(+) T cells, the constitutive expression of the integrin α4β7 that effects their entry into GALT is downregulated following infection of mice with Salmonella typhimurium. We further show that this downregulation is dependent on TLR signaling, and that the TLR-activated naive CD8(+) T cells are blocked from entering GALT. This contrasts strongly with Ag-experienced effector T cells, for which TLR costimulation in the GALT potently upregulates α4β7 and enhances trafficking to intestinal tissues. Thus, TLR activation leads to opposite effects on migration of naive and effector CD8(+) T cells. Our data identify a mechanism that excludes noncognate CD8(+) T cells from selected immune compartments during TLR-induced systemic inflammation.
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http://dx.doi.org/10.4049/jimmunol.1202280DOI Listing
May 2013

Cellular immunostimulation by CpG-sequence-coated DNA origami structures.

ACS Nano 2011 Dec 23;5(12):9696-702. Epub 2011 Nov 23.

Center for Nanoscience and Department of Physics, Ludwig-Maximilians-Universität, Geschwister-Scholl-Platz 1, 80539 München, Germany.

To investigate the potential of DNA origami constructs as programmable and noncytotoxic immunostimulants, we tested the immune responses induced by hollow 30-helix DNA origami tubes covered with up to 62 cytosine-phosphate-guanine (CpG) sequences in freshly isolated spleen cells. Unmethylated CpG sequences that are highly specific for bacterial DNA are recognized by a specialized receptor of the innate immune system localized in the endosome, the Toll-like receptor 9 (TLR9). When incubated with oligonucleotides containing CpGs, immune cells are stimulated through TLR9 to produce and secrete cytokine mediators such as interleukin-6 (IL-6) and interleukin-12p70 (IL-12p70), a process associated with the initiation of an immune response. In our studies, the DNA origami tube built from an 8634 nt long variant of the commonly used single-stranded DNA origami scaffold M13mp18 and 227 staple oligonucleotides decorated with 62 CpG-containing oligonucleotides triggered a strong immune response, characterized by cytokine production and immune cell activation, which was entirely dependent on TLR9 stimulation. Such decorated origami tubes also triggered higher immunostimulation than equal amounts of CpG oligonucleotides associated with a standard carrier system such as Lipofectamine. In the absence of CpG oligonucleotides, cytokine production induced by the origami tubes was low and was not related to TLR9 recognition. Fluorescent microscopy revealed localization of CpG-containing DNA origami structures in the endosome. The DNA constructs showed in contrast to Lipofectamine no detectable toxicity and did not affect the viability of splenocytes. We thus demonstrate that DNA origami constructs represent a delivery system for CpG oligonucleotides that is both efficient and nontoxic.
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http://dx.doi.org/10.1021/nn203161yDOI Listing
December 2011

Systemic cancer therapy with a small molecule agonist of toll-like receptor 7 can be improved by circumventing TLR tolerance.

Cancer Res 2011 Aug 22;71(15):5123-33. Epub 2011 Jun 22.

Department of Internal Medicine, Ludwig-Maximilian University of Munich, Munich, Germany.

Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-α production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-3903DOI Listing
August 2011

Delivery of immunostimulatory RNA oligonucleotides by gelatin nanoparticles triggers an efficient antitumoral response.

J Immunother 2010 Nov-Dec;33(9):935-44

Center for Integrated Protein Science Munich and Division of Clinical Pharmacology, Ludwig-Maximilian University of Munich, Munich, Germany.

RNA oligonucleotides have emerged as a new class of biologicals that can silence gene expression but also stimulate immune responses through specific pattern-recognition receptors. The development of effective delivery systems remains a major challenge for the therapeutic application of the RNA oligonucleotides. In this study, we have established a novel biodegradable carrier system that is highly effective for the delivery of immunostimulatory RNA oligonucleotides. Formulation of RNA oligonucleotides with cationized gelatin nanoparticles potentiates immune activation through the Toll-like receptor 7 (TLR7) in both myeloid and plasmacytoid dendritic cells. Further, nanoparticle-delivered RNA oligonucleotides trigger production of the antitumoral cytokines IL-12 and IFN-α. Binding to gelatin nanoparticles protects RNA oligonucleotides from degradation by nucleases, facilitates their uptake by dendritic cells, and targets these nucleic acids to the endosomal compartment in which they are recognized by TLR7. In these effects, the nanoparticles are superior to the conventional transfection reagents lipofectamine, polyethylenimine, and DOTAP. In vivo, the delivery of TLR7-activating RNA oligonucleotides by gelatin nanoparticles triggers antigen-specific CD8+ T-cell and antibody responses. Indeed, immunization with RNA-loaded nanoparticles leads to an efficient antitumoral immune response in two different mouse tumor models. Thus, gelatin-based nanoparticles represent a novel delivery system for immunostimulatory RNA oligonucleotides that is both effective and nontoxic.
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http://dx.doi.org/10.1097/CJI.0b013e3181f5dfa7DOI Listing
May 2011
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