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Article ; Online: Author Correction: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.

Huang, Yu-Hwa / Zhu, Chen / Kondo, Yasuyuki / Anderson, Ana C / Gandhi, Amit / Russell, Andrew / Dougan, Stephanie K / Petersen, Britt-Sabina / Melum, Espen / Pertel, Thomas / Clayton, Kiera L / Raab, Monika / Chen, Qiang / Beauchemin, Nicole / Yazaki, Paul J / Pyzik, Michal / Ostrowski, Mario A / Glickman, Jonathan N / Rudd, Christopher E /

Ploegh, Hidde L / Franke, Andre / Petsko, Gregory A / Kuchroo, Vijay K / Blumberg, Richard S

Nature

2024 Volume 626, Issue 8001, Page(s) E19

Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Published Erratum
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07164-y
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Baldrich, Adrian / Althaus, Dominic / Menter, Thomas / Hirsiger, Julia R / Köppen, Julius / Hupfer, Robin / Juskevicius, Darius / Konantz, Martina / Bosch, Angela / Drexler, Beatrice / Gerull, Sabine / Ghosh, Adhideb / Meyer, Benedikt J / Jauch, Annaise / Pini, Katia / Poletti, Fabio / Berkemeier, Caroline M / Heijnen, Ingmar / Panne, Isabelle /

Cavelti-Weder, Claudia / Niess, Jan Hendrik / Dixon, Karen / Daikeler, Thomas / Hartmann, Karin / Hess, Christoph / Halter, Jörg / Passweg, Jakob / Navarini, Alexander A / Yamamoto, Hiroyuki / Berger, Christoph T / Recher, Mike / Hruz, Petr

Journal of clinical immunology

2024 Volume 44, Issue 3, Page(s) 63

Abstract: ... encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being ... absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and ... in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic ...

Abstract	Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.
MeSH term(s)	Humans ; Cytokines/metabolism ; Hepatitis A Virus Cellular Receptor 2/genetics ; Inflammatory Bowel Diseases/diagnosis ; Inflammatory Bowel Diseases/etiology ; Intestinal Mucosa ; Stem Cell Transplantation/adverse effects
Chemical Substances	Cytokines ; Hepatitis A Virus Cellular Receptor 2
Language	English
Publishing date	2024-02-16
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-024-01667-z
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Article ; Online: Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis.

Cancer research

2022 Volume 82, Issue 20, Page(s) 3774–3784

Abstract: T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens ... effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under ... investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here ...

Abstract	T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition. Significance: Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.
MeSH term(s)	Animals ; Carcinogenesis ; Cell Transformation, Neoplastic ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Immunoglobulins ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Mucins
Chemical Substances	Hepatitis A Virus Cellular Receptor 2 ; Immunoglobulins ; Mucins
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-0970
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Article: TIM-3 Qualifies as a Potential Immunotherapeutic Target in Specific Subsets of Patients with High-Risk Soft Tissue Sarcomas (HR-STS).

Berclaz, Luc M / Altendorf-Hofmann, Annelore / Lindner, Lars H / Burkhard-Meier, Anton / Di Gioia, Dorit / Dürr, Hans Roland / Klein, Alexander / Albertsmeier, Markus / Schmidt-Hegemann, Nina-Sophie / Klauschen, Frederick / Knösel, Thomas

Cancers

2023 Volume 15, Issue 10

Abstract: 1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM ... tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination ... in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods ...

Abstract	(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (
Language	English
Publishing date	2023-05-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15102735
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Article ; Online: Nutzung von Routinedaten unterschiedlicher gesetzlicher Krankenkassen: Ein Erfahrungsbericht aus der TIM-HF2-Studie zur Datenerschließung, -validierung und -aufbereitung.

Winkler, Hanna / Koehler, Friedrich / Reinhold, Thomas / Willich, Stefan N / Prescher, Sandra

Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz

2023 Volume 66, Issue 9, Page(s) 1000–1007

Abstract: Background: The randomized controlled clinical trial "TIM-HF2" investigated the benefit ... processing in the TIM-HF2 trial. Based on the identification of potential problems for data completeness and ... Discussion: Based on the experience of the TIM-HF2 trial, a high heterogeneity has been detected ...

Title translation	Utilization of routine data from different statutory health insurance funds: a practical report of experience from the TIM-HF2 study about data acquisition, validation, and processing.
Abstract	Background: The randomized controlled clinical trial "TIM-HF2" investigated the benefit of telemonitoring in chronic heart failure. The health economic evaluation of this intervention was based on routine data from statutory health insurance (SHI) funds. Since participants were recruited independently of their SHI affiliation, there was a large number of potential data-providing SHI funds. This resulted in both organizational and methodological challenges, from participation of the data providers to data preparation. Method: The procedures are described from study planning and data acquisition to data review and processing in the TIM-HF2 trial. Based on the identification of potential problems for data completeness and data quality, possible solutions have been derived. Results: In total, participants were insured with 49 different SHI funds, which provided routine data for a total of 1450 participants. About half of all initial data deliveries were correct. The most common problems in data preparation occurred in the machine readability of the data. Success factors for a high level of data completeness were close communication with the SHI funds and a high level of time and personnel commitment to intensive data checking and preparation. Discussion: Based on the experience of the TIM-HF2 trial, a high heterogeneity has been detected in data management and transmission of routine data. Universally applicable data descriptions are desired to improve data access, quality, and usability for research purposes.
MeSH term(s)	Humans ; Germany ; Insurance, Health ; National Health Programs ; Research Report ; Financial Management
Language	German
Publishing date	2023-06-30
Publishing country	Germany
Document type	Randomized Controlled Trial ; English Abstract ; Journal Article
ZDB-ID	1461973-8
ISSN	1437-1588 ; 1436-9990
ISSN (online)	1437-1588
ISSN	1436-9990
DOI	10.1007/s00103-023-03735-y
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Article ; Online: Frustration and folding of a TIM barrel protein.

Halloran, Kevin T / Wang, Yanming / Arora, Karunesh / Chakravarthy, Srinivas / Irving, Thomas C / Bilsel, Osman / Brooks, Charles L / Matthews, C Robert

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 33, Page(s) 16378–16383

Abstract: Triosephosphate isomerase (TIM) barrel proteins have not only a conserved architecture ... of sampling the entire energy landscape of TIM barrels and offer the possibility of a molecular-level ...

Abstract	Triosephosphate isomerase (TIM) barrel proteins have not only a conserved architecture that supports a myriad of enzymatic functions, but also a conserved folding mechanism that involves on- and off-pathway intermediates. Although experiments have proven to be invaluable in defining the folding free-energy surface, they provide only a limited understanding of the structures of the partially folded states that appear during folding. Coarse-grained simulations employing native centric models are capable of sampling the entire energy landscape of TIM barrels and offer the possibility of a molecular-level understanding of the readout from sequence to structure. We have combined sequence-sensitive native centric simulations with small-angle X-ray scattering and time-resolved Förster resonance energy transfer to monitor the formation of structure in an intermediate in the
MeSH term(s)	Amino Acid Sequence ; Fluorescence Resonance Energy Transfer ; Indole-3-Glycerol-Phosphate Synthase/chemistry ; Indole-3-Glycerol-Phosphate Synthase/genetics ; Models, Molecular ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Scattering, Small Angle ; Sulfolobus solfataricus/enzymology ; Thermodynamics ; Triose-Phosphate Isomerase/chemistry ; Triose-Phosphate Isomerase/genetics
Chemical Substances	Indole-3-Glycerol-Phosphate Synthase (EC 4.1.1.48) ; Triose-Phosphate Isomerase (EC 5.3.1.1)
Language	English
Publishing date	2019-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1900880116
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Book: Tim Flach - Evolution

Flach, Tim / Osterkorn, Thomas

(Portfolio ; 74 ; Stern : Fotografie ; 74)

2013

Title variant	Evolution
Author's details	[Hrsg.: Thomas Osterkorn ...]
Series title	Portfolio ; 74 Stern : Fotografie ; 74
Language	German ; English
Size	[48] Bl., überw. Ill.
Publisher	Gruner + Jahr
Publishing place	Hamburg
Document type	Book
Note	Text dt. und engl.
ISBN	3652001583 ; 9783652001588
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: Tim-3 is dispensable for allergic inflammation and respiratory tolerance in experimental asthma.

Boehne, Carolin / Behrendt, Ann-Kathrin / Meyer-Bahlburg, Almut / Boettcher, Martin / Drube, Sebastian / Kamradt, Thomas / Hansen, Gesine

PloS one

2021 Volume 16, Issue 4, Page(s) e0249605

Abstract: T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been described ... In the present study we therefore directly examined the role of Tim-3 in allergic inflammation and respiratory ... tolerance. First, Tim-3-/- mice and wild type controls were immunized and challenged with the model allergen ...

Abstract	T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been described as a transmembrane protein, expressed on the surface of various T cells as well as different cells of innate immunity. It has since been associated with Th1 mediated autoimmune diseases and transplantation tolerance studies, thereby indicating a possible role of this receptor in counter-regulation of Th2 immune responses. In the present study we therefore directly examined the role of Tim-3 in allergic inflammation and respiratory tolerance. First, Tim-3-/- mice and wild type controls were immunized and challenged with the model allergen ovalbumin (OVA) to induce an asthma-like phenotype. Analysis of cell numbers and distribution in the bronchoalveolar lavage (BAL) fluid as well as lung histology in H&E stained lung sections demonstrated a comparable degree of eosinophilic inflammation in both mouse strains. Th2 cytokine production in restimulated cell culture supernatants and serum IgE and IgG levels were equally increased in both genotypes. In addition, cell proliferation and the distribution of different T cell subsets were comparable. Moreover, analysis of both mouse strains in our respiratory tolerance model, where mucosal application of the model allergen before immunization, prevents the development of an asthma-like phenotype, revealed no differences in any of the parameters mentioned above. The current study demonstrates that Tim-3 is dispensable not only for the development of allergic inflammation but also for induction of respiratory tolerance in mice in an OVA-based model.
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0249605
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Article ; Online: Chimeric TIM-4 receptor-modified T cells targeting phosphatidylserine mediates both cytotoxic anti-tumor responses and phagocytic uptake of tumor-associated antigen for T cell cross-presentation.

Cieniewicz, Brandon / Bhatta, Ankit / Torabi, Damoun / Baichoo, Priya / Saxton, Mike / Arballo, Alexander / Nguyen, Linh / Thomas, Sunil / Kethar, Harini / Kukutla, Phanidhar / Shoaga, Omolola / Yu, Bi / Yang, Zhuo / Fate, Maria / Oliveira, Edson / Ning, Hongxiu / Corey, Lawrence / Corey, Daniel

Molecular therapy : the journal of the American Society of Gene Therapy

2023 Volume 31, Issue 7, Page(s) 2132–2153

Abstract: ... We engineered a chimeric engulfment receptor (CER)-1236, which combines the extracellular domain of TIM-4 ... TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T cell cytotoxic function ...

Abstract	To leverage complementary mechanisms for cancer cell removal, we developed a novel cell engineering and therapeutic strategy co-opting phagocytic clearance and antigen presentation activity into T cells. We engineered a chimeric engulfment receptor (CER)-1236, which combines the extracellular domain of TIM-4, a phagocytic receptor recognizing the "eat me" signal phosphatidylserine, with intracellular signaling domains (TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T cell cytotoxic function. CER-1236 T cells demonstrate target-dependent phagocytic function and induce transcriptional signatures of key regulators responsible for phagocytic recognition and uptake, along with cytotoxic mediators. Pre-clinical models of mantle cell lymphoma (MCL) and EGFR mutation-positive non-small cell lung cancer (NSCLC) demonstrate collaborative innate-adaptive anti-tumor immune responses both in vitro and in vivo. Treatment with BTK (MCL) and EGFR (NSCLC) inhibitors increased target ligand, conditionally driving CER-1236 function to augment anti-tumor responses. We also show that activated CER-1236 T cells exhibit superior cross-presentation ability compared with conventional T cells, triggering E7-specific TCR T responses in an HLA class I- and TLR-2-dependent manner, thereby overcoming the limited antigen presentation capacity of conventional T cells. Therefore, CER-1236 T cells have the potential to achieve tumor control by eliciting both direct cytotoxic effects and indirect-mediated cross-priming.
MeSH term(s)	Humans ; Adult ; T-Lymphocytes ; Cross-Priming ; Phosphatidylserines ; Carcinoma, Non-Small-Cell Lung ; Lung Neoplasms ; Antineoplastic Agents ; Antigens, Neoplasm ; ErbB Receptors ; Immunotherapy, Adoptive ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Phosphatidylserines ; Antineoplastic Agents ; Antigens, Neoplasm ; ErbB Receptors (EC 2.7.10.1) ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2023.05.009
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Article ; Online: Cost-effectiveness of noninvasive telemedical interventional management in patients with heart failure: health economic analysis of the TIM-HF2 trial.

Sydow, Hanna / Prescher, Sandra / Koehler, Friedrich / Koehler, Kerstin / Dorenkamp, Marc / Spethmann, Sebastian / Westerhoff, Benjamin / Wagner, Christoph J / Liersch, Sebastian / Rebscher, Herbert / Wobbe-Ribinski, Stefanie / Rindfleisch, Heike / Müller-Riemenschneider, Falk / Willich, Stefan N / Reinhold, Thomas

Clinical research in cardiology : official journal of the German Cardiac Society

2021 Volume 111, Issue 11, Page(s) 1231–1244

Abstract: ... mortality in the Telemedical Interventional Management in Heart Failure II trial (TIM-HF2). The health ... results: A total of 1538 participants of the TIM-HF2 randomized controlled trial were assigned to the RPM ... Usual Care group), which represents 94.3% of the original TIM-HF2 patient population, were linked ...

Abstract	Background: Noninvasive remote patient management (RPM) in patients with heart failure (HF) has been shown to reduce the days lost due to unplanned cardiovascular hospital admissions and all-cause mortality in the Telemedical Interventional Management in Heart Failure II trial (TIM-HF2). The health economic implications of these findings are the focus of the present analyses from the payer perspective. Methods and results: A total of 1538 participants of the TIM-HF2 randomized controlled trial were assigned to the RPM and Usual Care group. Health claims data were available for 1450 patients (n = 715 RPM group, n = 735 Usual Care group), which represents 94.3% of the original TIM-HF2 patient population, were linked to primary data from the study documentation and evaluated in terms of the health care cost, total cost (accounting for intervention costs), costs per day alive and out of hospital (DAOH), and cost per quality-adjusted life year (QALY). The average health care costs per patient year amounted to € 14,412 (95% CI 13,284-15,539) in the RPM group and € 17,537 (95% CI 16,179-18,894) in the UC group. RPM led to cost savings of € 3125 per patient year (p = 0.001). After including the intervention costs, a cost saving of € 1758 per patient year remained (p = 0.048). Conclusion: The additional noninvasive telemedical interventional management in patients with HF was cost-effective compared to standard care alone, since such intervention was associated with overall cost savings and superior clinical effectiveness.
MeSH term(s)	Humans ; Cost-Benefit Analysis ; Heart Failure/therapy ; Telemedicine/methods ; Hospitalization ; Health Care Costs ; Quality-Adjusted Life Years
Language	English
Publishing date	2021-12-11
Publishing country	Germany
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2213295-8
ISSN	1861-0692 ; 1861-0684
ISSN (online)	1861-0692
ISSN	1861-0684
DOI	10.1007/s00392-021-01980-2
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