B lymphocytes protect islet β cells in diabetes-prone NOD mice treated with imatinib

Wilson, Christopher; Spaeth, Jason M.; Karp, Jay; Stocks, Blair T.; Hoopes, Emilee M; Stein, Roland; Moore, Daniel J.

doi:10.1172/jci.insight.125317

Cited by 11 publications

(9 citation statements)

References 56 publications

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“…246 The islet-protecting action of imatinib requires B lymphocytes. 247 Individuals with T1D diabetes demonstrate a transition from autoimmune inflammation to atherosclerosis, a prime example of metabolic inflammation. 248,249 As mentioned earlier, we posed the question: Can NTM ameliorate metabolic inflammation?…”

Section: Inflammation: T Ype 1 Diabetesmentioning

confidence: 99%

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Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Hawiger

Zienkiewicz

2019

Scand J Immunol

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Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic and physical insults that produce distinct types of inflammatory responses. This aetiologic view of inflammation informs its classification based on a cause‐dependent mechanism as well as a cause‐directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the centre of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non‐immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors’ access to the nucleus. We present two approaches that control proinflammatory signalling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signalling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell‐penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the nine genes required for metabolic responses. We compare these emerging anti‐inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical and other types of inflammation afflicting millions of people worldwide.

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Section: Inflammation: T Ype 1 Diabetesmentioning

confidence: 99%

“…Alternatively, imatinib, an inhibitor of tyrosine kinases, reduces ER stress in pancreatic β cells and reverses autoimmune diabetes . The islet‐protecting action of imatinib requires B lymphocytes …”

Section: Autoimmune Inflammation: Type 1 Diabetesmentioning

confidence: 99%

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Hawiger

Zienkiewicz

2019

Scand J Immunol

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“…However, a broad range of adverse side-effects were reported and occurred more frequently in the imatinib-dosed group, categorized as gastrointestinal, skin, respiratory, cardiac, endocrine and infectious, suggesting a wide range of off-target effects. Indeed, it was recently reported that in addition to terminal UPR signaling, imatinib also directly affects insulin secretion from beta cells [ 62 ] and promotes reactive oxygen species (ROS) scavenging by B cells in NOD mice, an effect which is essential for diabetes reversal [ 63 ]. Thus, it would seem that there is still much to learn about the mechanisms of this drug.…”

Section: Beta Cell Dysfunction In T1dmentioning

confidence: 99%

Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

Brawerman

Thompson

2020

Biomolecules

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Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.

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“…2020;2(2):e200016. https://doi.org/10.20900/immunometab20200016 Immunometabolism 12 of 25investigation indicated that this antioxidant capacity was likely due to the action of the superoxide dismutase system (SOD1 and SOD2) and not through the glutathione peroxidase (GPx)[107]. This enhaced oxidative protection may be an intrinsic characteristic of all B cells in NOD mice or may be a consequence of some stage of negative selection in which only those cells with the greatest capacity to resist ROS-induced apoptosis survive.…”

mentioning

confidence: 99%

“…https://doi.org/10.20900/immunometab20200016 Immunometabolism 14 of 25 extracellular environment[107]. Enhanced B cell redox restored ROSsensitive Mafa in beta cells leading to improved insulin secretion and restoration of euglycemia but only when B cells were present[107]. This interaction illustrates the potential for excessive antioxidant metabolism among B cells in T1D.…”

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confidence: 99%

B Cell Metabolism: An Understudied Opportunity to Improve Immune Therapy in Autoimmune Type 1 Diabetes

Wilson

Moore

2020

Immunometabolism

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Although B lymphocytes are a key cell type that drives type 1 diabetes (T1D), therapeutic targeting of these cells has not ameliorated disease, and it has been impossible to eliminate autoantibody production clinically once it begins. This challenge indicates a need for further dissection of the cellular processes responsible for the development and activation of autoreactive B cells in T1D. Review of the literature in T1D and other autoimmune and hematopoietic diseases indicates that cellular metabolism contributes significantly to lymphocyte development and fate. Unfortunately, little is known about the normal metabolism of B cells and even less is known about the metabolism of B cells in T1D other than what can be inferred from other immune processes. Clues derived from the literature suggest B cell metabolism in T1D is altered including potential differences in OXPHOS, glucose metabolism, fatty-acid metabolism, and reactive-oxygen species stress response. Future research should dissect the metabolic processes at play in autoreactive B cells in T1D. Once understood, B cell metabolism will become a promising target to use in conjunction with current clinical therapies in T1D. Additionally, metabolic changes in B cells may serve as a reliable biomarker for predicting the responsiveness of patients to these immune therapies.

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B lymphocytes protect islet β cells in diabetes-prone NOD mice treated with imatinib

Cited by 11 publications

References 56 publications

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

B Cell Metabolism: An Understudied Opportunity to Improve Immune Therapy in Autoimmune Type 1 Diabetes

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