Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?

Carré, Alexia; Richardson, Sarah J.; Larger, Étienne; Mallone, Roberto

doi:10.1007/s00125-020-05298-y

Cited by 41 publications

(41 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Currently, evidence indicates that the rapid, aggressive disease developing in children is largely T cell-mediated. However, adult onset T1D may be driven by T cells, and/or innate effectors and/or β cell intrinsic defects leading to dysregulation of insulin production ( 236 ). Needed are sensitive disease readouts and biomarkers that distinguish between the respective scenarios or endotypes, to ensure that the appropriate therapeutic strategy is being applied ( 237 ).…”

Section: Discussionmentioning

confidence: 99%

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

et al. 2021

View full text Add to dashboard Cite

Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…It is clear that our understanding of T1D will continue to evolve and be refined due to advancements in experimental tools and approaches, such as high sensitivity immunohistochemistry [ 116 ], single cell phenotyping [ 87 ], image cytometry and high-throughput analysis [ 20 , 21 ], ultrasensitive hormone assays [ 19 ] and pancreas slice technology [ 47 ]. But progress will also depend on the willingness to challenge dogma and long-held assumptions about T1D [ 24 , 140 , 141 ]. It is on this foundation that the promise of therapies aiming to restore beta cell function and survival for preventing and treating T1D will eventually be fulfilled.…”

Section: Discussionmentioning

confidence: 99%

“…Our current knowledge gaps in T1D etiology, and the relative contributions of beta cell death and dysfunction on the one hand, and immune system dysfunction on the other, are areas where investigators are becoming more critical of long-held assumptions [ 29 ]. Indeed, some in the field are now calling for a total re-evaluation of T1D etiologies based on the concept of disease endotypes, involving predominantly immune versus predominantly beta cell-driven pathogenesis [ 139 , 140 , 141 ]. Accordingly, the field has already recognized other distinct, but as yet poorly understood forms of insulin-deficient T1D.…”

Section: Combining Beta Cell Therapy With Immunotherapy For T1d Prmentioning

confidence: 99%

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

Brawerman

Thompson

2020

Biomolecules

View full text Add to dashboard Cite

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.

show abstract

“…There is also growing evidence supporting the idea that beta-cell dysfunction is another key driver of T1D pathogenesis ( 2 ). The heterogeneity of pancreas histopathology between T1D donors and even across islets from the same pancreas, both in terms of immune infiltrates and residual beta cells, have led to the definition of age-related endotypes ( 3 ), in which the component of beta-cell dysfunction may be dominant in adult-onset cases ( 4 , 5 ). Effector CD8+ T cells recognize MHC Class I (MHC-I)-peptide complexes at the surface of beta cells.…”

Section: Introductionmentioning

confidence: 99%

Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum

Carré

Mallone

2021

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Autoimmune type 1 diabetes (T1D) results from the intricate crosstalk of various immune cell types. CD8+ T cells dominate the pro-inflammatory milieu of islet infiltration (insulitis), and are considered as key effectors of beta-cell destruction, through the recognition of MHC Class I-peptide complexes. The pathways generating MHC Class I-restricted antigens in beta cells are poorly documented. Given their specialized insulin secretory function, the associated granule processing and degradation pathways, basal endoplasmic reticulum stress and susceptibility to additional stressors, alternative antigen processing and presentation (APP) pathways are likely to play a significant role in the generation of the beta-cell immunopeptidome. As direct evidence is missing, we here intersect the specificities of beta-cell function and the literature about APP in other cellular models to generate some hypotheses on APPs relevant to beta cells. We further elaborate on the potential role of these pathways in T1D pathogenesis, based on the current knowledge of antigens presented by beta cells. A better understanding of these pathways may pinpoint novel mechanisms amenable to therapeutic targeting to modulate the immunogenicity of beta cells.

show abstract

Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?

Cited by 41 publications

References 78 publications

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

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

Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum

Contact Info

Product

Resources

About