Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation

Stocks, Blair T.; Thomas, Analise B.; Elizer, Sydney K.; Zhu, Yuantee; Marshall, Andrew; Wilson, Christopher; Moore, Daniel J.

doi:10.2337/db16-0444

Cited by 3 publications

(2 citation statements)

References 26 publications

(29 reference statements)

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“…We previously established that SLE123 mice resist transplant tolerance induced by a monoclonal antibody (MB23G2) that targets cell surface phosphatase CD45RB (28). Tolerance to transplantation was resisted by SLE123 mice even when the transplanted organ is not the target of recurrent autoimmunity as has also been observed in other autoimmune models (24,(29)(30)(31). To rule out the contribution of cellular abnormalities and activation that emerge later in the life of SLE123 mice, we assessed the response of 9-12 week old mice in this study prior to the detection of chronic immune cell activation.…”

Section: Anti-cd45rb Promotes Regulation Of the B And T Lymphocyte Compartment That Is Resisted In The Sle123 Mousementioning

confidence: 86%

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

Wilson¹,

Stocks²,

Hoopes³

et al. 2021

JCI Insight

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Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction.A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and also restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies. Significance StatementFine tuning of the immune response is critical to health. This fine tuning is lost in autoimmunity and cancer and must be restored to prevent undesirable outcomes. Immune cell metabolism can regulate the immune response but to date chronic interventions have been needed to produce any biologic effect. Our study in lupus-prone animals demonstrates that disease-associated changes in immune cell metabolism create a barrier to immune tolerance, which can be reset by short term metabolic treatment with 2-deoxyglucose and metformin. Metabolic therapy restored normal expression of extracellular receptors, which was required for successful immune therapy.These findings reveal the role of glycoregulation in the immune response and indicate an important interaction between immune metabolism and responsiveness to immune therapy. the spleen (Figure 1 B&C) (33). Anti-CD45RB treatment leads to a B cell dependent expansion of CD4+ Foxp3+ Tregs to promote longterm tolerance induction (23,32). We hypothesized that this B cell mobilization would expand CD4+ Foxp3+ Tregs in both SLE123 and B6 mice. Analysis of the Foxp3 + and CD25 + fractions of the CD4 + population revealed expansion of Tregs in both B6 and SLE123 mice following anti-CD45RB therapy (Figure 1 D&E). Anti-CD45RB uncovers inappropriate effector responses to tolerogenic signaling.While expansion of Tregs is important for long-term tolerance in anti-CD45RB treatment, the effector compartment must also be temporarily modulated to facilitate adequate regulation (34,35). In healthy B6 mice, anti-CD45RB inhibits the Germinal Center (GC) response and temporarily cripples antibody production (28,35). In clinical SLE and in the mouse model of disease, there is an expansion of T-follicular helper (Tfh) cells and GC B cells that collaborate to generate autoantibodies that occlude and damage the nephron...

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Section: Anti-cd45rb Promotes Regulation Of the B And T Lymphocyte Compartment That Is Resisted In The Sle123 Mousementioning

confidence: 86%

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

Wilson¹,

Stocks²,

Hoopes³

et al. 2021

JCI Insight

Self Cite

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“…126 This is suggested to severely affect the clinical outcomes in diabetic patients undergoing islet or stem cell transplant. 127 Furthermore, bone marrow is a rich source for circulating vascular progenitor cells, whose mobilisation is also known to be negatively modulated in diabetes. 128 Considering that the overall HSC numbers in circulation under diabetes are reduced, strategies to mobilise HSCs are being researched as potential therapies for diabetes-related complications.…”

Section: Stem Cell Mobilisation Strategiesmentioning

confidence: 99%

Therapies for Type 1 Diabetes: Current Scenario and Future Perspectives

Pathak

O'Neill

et al. 2019

Clin Med Insights Endocrinol Diabetes

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Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing β cells located in the endocrine pancreas in areas known as islets of Langerhans. The current standard-of-care for T1D is exogenous insulin replacement therapy. Recent developments in this field include the hybrid closed-loop system for regulated insulin delivery and long-acting insulins. Clinical studies on prediction and prevention of diabetes-associated complications have demonstrated the importance of early treatment and glucose control for reducing the risk of developing diabetic complications. Transplantation of primary islets offers an effective approach for treating patients with T1D. However, this strategy is hampered by challenges such as the limited availability of islets, extensive death of islet cells, and poor vascular engraftment of islets post-transplantation. Accordingly, there are considerable efforts currently underway for enhancing islet transplantation efficiency by harnessing the beneficial actions of stem cells. This review will provide an overview of currently available therapeutic options for T1D, and discuss the growing evidence that supports the use of stem cell approaches to enhance therapeutic outcomes.

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Diabetes mellitus as a poor mobilizer condition

Fadini

DiPersio

2018

Blood Reviews

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Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation

Cited by 3 publications

References 26 publications

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

Therapies for Type 1 Diabetes: Current Scenario and Future Perspectives

Diabetes mellitus as a poor mobilizer condition

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