Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

Ostrov, David A.; Alkanani, Aimon K.; McDaniel, Kristen A.; Case, Stephanie; Baschal, Erin E.; Pyle, Laura; Ellis, Samuel L.; Pöllinger, Bernadette; Seidl, Katherine J.; Shah, Viral N.; Garg, Satish K.; Atkinson, Mark A.; Gottlieb, Peter A.; Michels, Aaron

doi:10.1172/jci97739

Cited by 43 publications

(31 citation statements)

References 64 publications

(68 reference statements)

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“…This is likely due to other islet-specific CD4 + T cells being unaffected by Ins4G8 treatment or due to islet-specific CD8 + T cells, which would be unaffected by Ins4G8 as they are not MHCII-restricted. Recent work has shown that methyldopa has the ability to block insB 10-23 but not viral peptide docking in the context of the DQ8 molecule in T1D patients (55). We speculate that Abs targeting multiple self-peptide:MHC class I and II complexes, compounds like methyldopa, Ag-coupled nanoparticles (56), or Ag-coupled apoptotic splenocytes (57) could limit the autoimmune side effects of checkpoint blockade in at-risk patients while still allowing antitumor immunity to reboot and eradicate tumors.…”

Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes

Martinov

Swanson

Breed

et al. 2019

The Journal of Immunology

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Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers (GC) is controversial. To address the role of PD-1 in the GC reaction in type 1 diabetes, we used tetramers to phenotype insulinspecific CD4 + T and B cells in NOD mice. PD-1 or PD-L1 deficiency, and PD-1 but not PD-L2 blockade, unleashed insulinspecific T follicular helper CD4 + T cells and enhanced their survival. This was concomitant with an increase in GC B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on the GC was reduced when mice were treated with a mAb targeting the insulin peptide:MHC class II complex. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition and suggests that targeting the self-peptide:MHC class II complex might limit autoimmunity arising from checkpoint blockade.

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Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes

Martinov

Swanson

Breed

et al. 2019

The Journal of Immunology

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“…Insulin is an early immune target in T1D; moreover, insulin autoantibody positivity has been associated with HLA DQ8 positivity 38 , 39 . In a small study of HLA-DQ8 + patients with recent-onset T1D, methyldopa was shown to specifically block insulin peptide binding to HLA-DQ8 and to decrease inflammatory T-cell responses to insulin 40 . TrialNet aims to launch a similar study testing the effects of methyldopa on antigen presentation in a DQ8 + at-risk population of children and adults with insulin antibodies 41 .…”

Section: Immunotherapy Work and Is Safementioning

confidence: 99%

Insulin is necessary but not sufficient: changing the therapeutic paradigm in type 1 diabetes

Lord

2020

F1000Res

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Despite the clear evidence that type 1 diabetes (T1D) begins well before hyperglycemia is evident, there are no clinically available disease-modifying therapies for early-stage disease. However, following the exciting results of the Teplizumab Prevention Study, the first study to demonstrate that overt T1D can be delayed with immunotherapy, there is renewed optimism that in the future, T1D will be treated before hyperglycemia develops. A different treatment paradigm is needed, as a majority of people with T1D do not meet the glycemic targets that are associated with a lower risk of T1D complications and therefore remain vulnerable to complications and shortened life expectancy. The following review will outline the history and current status of immunotherapy for T1D and highlight some challenges and ideas for the future. Although such efforts have been worldwide, we will focus particularly on the activities of Diabetes TrialNet, a National Institutes of Health consortium launched in 2004.

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“…DQ8 is present in 50–60% of people with TID and of those at risk. Preclinical studies [87] and a phase 1b escalation study [88] suggest that methyldopa can safely and durably block antigen presentation in this fashion. Trial Net aims to launch a study to evaluate the ability of methyldopa to block ongoing immune destruction of beta cells in relatives at risk of TID [89].…”

Section: Immunotherapy For Tidmentioning

confidence: 99%

Disease-Modifying Therapies in Type 1 Diabetes: A Look into the Future of Diabetes Practice

Greenbaum

VanBuecken

2019

Drugs

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The novel understanding that the presence of multiple islet autoantibodies, indicating islet autoimmunity, inevitably leads to type 1 diabetes (T1D) has necessitated the development of a new staging classification system for the condition. Coupled with an improved understanding of the disease course, the realization that T1D appears to be more heterogeneous than previously thought has led to unique opportunities to develop more targeted therapies that may be applied even before the onset of dysglycemia or symptoms. To date, several therapies have been trialed to delay or halt disease progression in both presymptomatic and clinical T1D, each demonstrating varying degrees of effectiveness, toxicity, and utility. Key research supports the eventual implementation of immunotherapy in autoimmune diabetes, potentially calling for a paradigm shift among care providers. It will likely be necessary to develop new approaches to trial design and to address potential barriers to progress before an effective treatment for the disease may be achieved.

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Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

Cited by 43 publications

References 64 publications

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes

Insulin is necessary but not sufficient: changing the therapeutic paradigm in type 1 diabetes

Disease-Modifying Therapies in Type 1 Diabetes: A Look into the Future of Diabetes Practice

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