Immune Intervention and Replacement Therapies in Type 1 Diabetes.

Diabetes Technology & TherapeuticsVol. 25, No. S1 Original ArticlesFree AccessImmune Intervention and Replacement Therapies in Type 1 DiabetesBimota Nambam, Nataša Bratina, and Desmond SchatzBimota NambamDepartment of Pediatrics, Division of Endocrinology, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.Search for more papers by this author, Nataša BratinaUniversity Medical Centre, University Children's Hospital Ljubljana, Department of Endocrinology, Diabetes and Metabolic Diseases, Ljubljana, Slovenia.Search for more papers by this author, and Desmond SchatzDepartment of Pediatrics, Division of Endocrinology, University of Florida, Gainesville, FL, USA.Search for more papers by this authorPublished Online:20 Feb 2023https://doi.org/10.1089/dia.2023.2513AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionIn recent years, researchers have conducted extensive, well-designed studies aimed at preserving beta (β) cell function in those with new-onset type 1 diabetes (T1D) or delaying progression to disease in those at risk. Two immunomodulatory agents that have been very promising include teplizumab (both in at-risk and new onset T1D) and low dose anti-thymocyte globulin (ATG) (in new onset T1D). In addition to these, verapamil has also demonstrated β cell preservation. Recent studies have also highlighted the potential of stem cell therapies as a viable means of reversing T1D. However, it is well recognized that stem cell–derived islet cells are still potentially at risk for subsequent autoimmune attack. Effective microencapsulation and macroencapsulation techniques could shield patients from subsequent autoimmunity. Recent studies have demonstrated that the β cell itself, by virtue of its inherent properties (including its high vascularity, vulnerability to endoplasmic reticulum [ER] dysfunction, defective insulin secretion, etc.), may be complicit in its own autoimmune destruction. Therefore, manipulation of ER function and other oxidative stress pathways may provide new strategies for T1D treatment, including stem cell therapy.Key Articles ReviewedExploratory Study Reveals Far Reaching Systemic and Cellular Effects of Verapamil Treatment in Subjects with Type 1 DiabetesXu G, Grimes TD, Grayson TB, Chen J, Thielen LA, Tse HM, Li P, Kanke M, Lin T-T, Schepmoes AA, Swensen AC, Petyuk VA, Ovalle F, Sethupathy P, Qian W-J, Shalev ANat Commun 2022;13: 1159Study Protocol: Minimum Effective Low Dose: Anti-Human Thymocyte Globulin (MELD-ATG): Phase II, Dose Ranging, Efficacy Study of Antithymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 DiabetesWilhelm-Benartzi CS, Miller SE, Bruggraber S, Picton D, Wilson M, Gatley K, Chhabra A, Marcovecchio ML, Hendriks AEJ, Morobé H, Chmura PJ, Bond S, Aschemeier-Fuchs B, Knip M, Tree T, Overbergh L, Pall J, Arnaud O, Haller MJ, Nitsche A, Schulte AM, Mathieu C, Mander A, Dunger DBMJ Open 2021;11: e053669Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T CellsLeung SS, Borg DJ, McCarthy DA, Boursalian TE, Cracraft J, Zhuang A, Fotheringham AK, Flemming N, Watkins T, Miles JJ, Groop P, Scheijen JL, Schalkwijk CG, Steptoe RJ, Radford KJ, Knip M, Forbes JMDiabetes 2022;71: 1994–2008Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating DiabetesTahbaz M, Yoshihara EFront Immunol 2021;12: 756548An Autoimmune Stem-Like CD8 T Cell Population Drives Type 1 DiabetesGearty SV, Dündar F, Zumbo P, Espinosa-Carrasco G, Shakiba M, Sanchez-Rivera FJ, Socci ND, Trivedi P, Lowe SW, Lauer P, Mohibullah N, Viale A, DiLorenzo TP, Betel D, Schietinger ANature 2022;602(7895): 156–161Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes PathogenesisToren E, Burnette KS, Banerjee R, Hunter CS, Tse HMFront Immunol 2021;12: 756548Exploratory Study Reveals Far Reaching Systemic and Cellular Effects of Verapamil Treatment in Subjects with Type 1 DiabetesXu G1,2, Grimes TD1,2, Grayson TB1,2, Chen J1,2, Thielen LA1,2, Tse HM1,3, Li P1,4, Kanke M5, Lin T-T6, Schepmoes AA6, Swensen AC6, Petyuk VA6, Ovalle F1,2, Sethupathy P5, Qian W-J6, Shalev A1,21Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL; 2Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL; 3Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL; 4School of Nursing, University of Alabama at Birmingham, Birmingham, AL; 5Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY; 6Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WANat Commun 2022;13: 1159BackgroundPrevious studies (1,2) have suggested that verapamil may preserve β cell function. Verapamil, a known antihypertensive calcium channel blocker, has been shown to decrease the expression of thioredoxin-interacting protein (TXNIP), promoting the survival of insulin-producing β cells and leading to diabetes reversal in mouse models. In the initial randomized, double-blind, placebo-controlled, phase 2 clinical trial, the efficacy and safety of verapamil given orally for 12 months was assessed in a small group of adult participants with recently diagnosed type 1 diabetes (T1D). Verapamil treatment was well tolerated and, compared to the placebo, associated with less hypoglycemia, less insulin use, and better C-peptide levels after mixed meal tolerance testing (MMTT). This study sought to understand potential mechanisms of action and durability and to identify potential responder biomarkers.MethodsParticipants with T1D who were positive for T1D-associated autoantibodies and diagnosed within 3 months were randomly assigned verapamil (360 mg sustained-release daily) or placebo in a blinded fashion for 1 year as described in the protocol of the initial trial (https://www.clinicaltrials.gov/ct2/show/NCT02372253); participants were then continued on or off verapamil and followed for a second year. Five participants continued to receive verapamil for 2 years, four participants discontinued the active study drug, and six participants were randomized to the control arm over the 2-year period. Twenty samples from 10 participants (five for verapamil baseline, five for verapamil year 1, five for control baseline, five for control year 1) were collected. Proteomic analysis was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum samples from participants collected at baseline and after 1 year of receiving verapamil or placebo.ResultsFifty-three proteins were found to be significantly altered by verapamil over time (P<.05). There was enrichment for genes involved in neutrophil-mediated immunity, acute inflammatory and humoral immune responses, and cellular metabolic processes. Chromogranin A (CHGA, localized in secretory granules of pancreatic β cells) was significantly downregulated and was inversely correlated with C-peptide area under the curve (AUC). CHGA levels rose in participants taking verapamil for the first 12 months but declined after verapamil was discontinued. Expression of CXCR5 (a surface marker of proinflammatory T follicular helper [Tfh] cells) and expression of the Tfh signature cytokine interleukin 21 (IL21) were significantly higher in peripheral blood mononuclear cells (PBMC) of participants with T1D when compared to healthy controls and were lowered by verapamil treatment. Other genes involved in oxidative stress, apoptosis, and T1D autoimmunity were also significantly impacted by verapamil. Thioredoxin-interacting protein (TXNIP), a potential key factor in diabetes-associated β cell apoptosis, was downregulated.ConclusionOral verapamil in adults with T1D may delay disease progression, preserve endogenous β cell function, and lower insulin requirements for 2 years after diagnosis. Verapamil leads to improved serum CHGA levels and decreases levels of proinflammatory IL-21 and Tfh cell markers. It regulates the thioredoxin system and appears to promote an antioxidative, antiapoptotic, and immunomodulatory gene expression profile in human islets, suggesting that these changes may be associated with the overall clinically beneficial effects of verapamil administration in T1D.CommentsThis study demonstrated that verapamil induces many changes in both proteomic and immunologic profiles in those with T1D and that the drug delayed disease progression for 2 years. However, these findings remain to be validated in larger studies (both in children and adults). This study also highlighted the potential use of serum CHGA as a novel biomarker, since it showed good correlation with loss of β cell function and response to verapamil therapy.Study Protocol: Minimum Effective Low Dose: Anti-Human Thymocyte Globulin (MELD-ATG): Phase II, Dose Ranging, Efficacy Study of Antithymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 DiabetesWilhelm-Benartzi CS1, Miller SE2,3, Bruggraber S2, Picton D2, Wilson M2, Gatley K3, Chhabra A4, Marcovecchio ML2, Hendriks AEJ2, Morobé H5, Chmura PJ6, Bond S3, Aschemeier-Fuchs B7, Knip M8,9, Tree T10, Overbergh L5, Pall J11, Arnaud O12, Haller MJ13, Nitsche A14, Schulte AM14, Mathieu C5, Mander A1, Dunger D2,151Centre for Trials Research, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 2Department of Paediatrics, University of Cambridge, Cambridge, UK; 3Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 4Pharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 5Katholieke Universiteit Leuven/Universitaire Ziekenhuizen, Leuven, Belgium; 6Center for Protein Research, Kobenhavns Universitet Sundhedsvidenskabelige Fakultet, Kobenhavn, Denmark; 7Diabetes Centre for Children and Adolescents, Children's Hospital Auf der Bult, Hannover, Germany; 8Research Program for Clinical and Molecular Metabolism, University of Helsinki Faculty of Medicine, Helsinki, Finland; 9Pediatric Research Centre, University of Helsinki Children's Hospital, Helsinki, Finland; 10Department of Immunobiology, King's College London, London, UK; 11INNODIA Patient Advisory Committee, Madrid, Spain; 12INNODIA Patient Advisory Committee, Paris, France; 13Department of Pediatrics, University of Florida, Gainesville, FL; 14Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany; 15Wellcome Trust-MRC Institute of Metabolic Science, Cambridge University, Cambridge, UKBMJ Open 2021;11: e053669BackgroundStudies by Haller et al. have demonstrated that low dose antithymocyte globulin (ATG) at 2.5 mg/kg has the potential to prevent β cell functional decline in newly diagnosed type 1 diabetes (T1D) (12–45 years). Surprisingly, another study that investigated the use of ATG in newly diagnosed T1D patients, but at a higher dose of 6.5 mg/kg, failed to show benefits. This study, to be conducted in the INNODIA network, will seek to assess the efficacy and tolerability of not only a 2.5 mg/kg ATG dose, but also of lower doses in the pediatric and adult populations with new onset T1D. Furthermore, they will seek potential mechanistic effects of ATG administration.MethodsThis is a phase 2, randomized, placebo-controlled, multi-arm parallel group trial in those with new onset T1D (5–25 years and within 3–9 weeks of start of treatment with ATG, N=114). Participants will be enrolled into seven different cohorts. The first cohort (n=30, 12–25 years) will be randomized to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg, and 0.1 mg/kg. The next six cohorts (n=12–15 in each cohort, 5–25 years) will be randomized to placebo, 2.5 mg/kg, and one of two selected middle ATG doses. Middle doses will be adjusted for each cohort after review of efficacy and toxicity data of the preceding cohorts. Participants in each cohort will be followed at 1, 2, and 4 weeks, and at 3, 6, and 12 months after treatment.ResultsThe primary outcome is a change in AUC stimulated C-peptide (after MMTT) of 2.5 mg/kg vs placebo and, if there is a statistical difference between the two arms, to identify a minimally effective dose that is statistically different from placebo in the middle doses. The lowest dose below 2.5 mg/kg that is statistically different from placebo will be declared the minimally effective low dose (MELD).ConclusionLow-dose ATG has demonstrated potential for β cell preservation in new onset T1D patients. The current study will investigate if it has the same potential in lower doses and identify potential mechanisms of action.CommentsReversal of T1D remains elusive. Monotherapeutic agents such as teplizumab have been investigated recently with good outcomes for those with new onset, as well as in at-risk patients. Low-dose ATG can be given over a short period and has similar efficacy in new-onset patients at 1 and 2 years after diagnosis and would likely be cheaper; hence, it is primed for prevention intervention studies. We look forward to seeing whether an even lower ATG dose will have similar efficacy even in children, have a greater safety profile, and will give more insight into potential mechanisms of action.Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T CellsLeung SS1,2, Borg DJ1,3, McCarthy DA1, Boursalian TE4, Cracraft J4, Zhuang A1, Fotheringham AK1,2, Flemming N1,2, Watkins T5, Miles JJ5, Groop P6,7,8,9, Scheijen JL10,11, Schalkwijk CG10,11, Steptoe RJ12, Radford KJ2,13, Knip M6,14, Forbes JM1,9,151Glycation and Diabetes, Mater Research Institute - The University of Queensland (MRI-UQ), Translational Research Institute (TRI), Brisbane, Australia; 2School of Biomedical Sciences, The University of Queensland, Brisbane, Australia; 3Inflammatory Disease Biology and Therapeutics, MRI-UQ, TRI, Brisbane, Australia; 4Type 1 Diabetes Research Center, Novo Nordisk, Seattle, WA; 5Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, Australia; 6Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 7Folkhälsan Research Center, Helsinki, Finland; 8Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 9Baker IDI Heart and Diabetes Institute, Melbourne, Australia; 10Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University, LK Maastricht, The Netherlands; 11Cardiovascular Research Institute Maastricht, ER Maastricht, The Netherlands; 12The University of Queensland Diamantina Institute, TRI, Brisbane, Australia; 13Cancer Immunotherapies, MRI-UQ, TRI, Brisbane, Australia; 14Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 15Mater Clinical School, The University of Queensland, Brisbane, AustraliaDiabetes 2022;71: 1994–2008BackgroundThe receptor for advanced glycation end products (RAGE), a receptor implicated in inflammatory diseases, is expressed in various cells involved in the pathogenesis of type 1 diabetes (T1D). Polymorphisms in the RAGE gene decrease circulating soluble RAGE (sRAGE) and increase the risk for T1D in at-risk individuals. These decreases in circulating sRAGE are associated with the formation of autoantibodies against islet autoantigens in individuals at risk for developing T1D. The authors of this study have hypothesized that deficiency in circulating sRAGE presents a pathway to finding a novel therapeutic target for preventing the onset of T1D.MethodsNon-obese diabetic mice (NOD) mice were randomized to intraperitoneal injections on days 50–64 of life with recombinant human sRAGE (25 μg) twice daily (study sites 1 and 2), vehicle (phosphate-buffered saline) twice daily (site1), sRAGE (100 μg) once daily (site 2), or untreated (site 2). Mice were fasted for 4–6 h and euthanized on day 64, 80, or, for nonprogressors, on day 225 of life. Biochemical and molecular studies were then carried out.ResultsRecombinant human sRAGE administered twice daily during the prediabetic phase for 2 weeks (day 50–64 of life) decreased the incidence of diabetes 3-fold by day 225 when compared with vehicle-treated mice. Mice treated with sRAGE had increasing proportions of Tregs in the islet infiltrating leukocytes, pancreatic lymph nodes (PLN), and spleen. Ex vivo, sRAGE led to expansion of human Tregs and reduced Tconv proliferation in co-culture, whereas Tregs cultured in the presence of the RAGE ligand (AGEs) had reduced suppressive function.ConclusionShort-term administration of sRAGE leads to functional Treg expansion, thereby preventing T1D diabetes in NOD mice.CommentsOther studies have shown that sRAGE is a native protein that is lower in children at risk of T1D, and the authors of this study have demonstrated successfully that short-term administration of sRAGE in NOD mice can prevent T1D. Nonetheless, it is still unknown whether such an effect can be replicated in humans.Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating DiabetesTahbaz M1, Yoshihara E1,21Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA; 2David Geffen School of Medicine at University of California, Los Angeles, CAFront Immunol 2021;12: 756548BackgroundAlthough clinical trials in the past have demonstrated that pancreatic islet transplantation can lead to significant glycemic control without hypoglycemia, the shortage of donors (human cadaveric islets) and the need for lifelong immunosuppression (directly toxic to β cells and, thus, diabetogenic) are the two main limitations of its use. Stem cell therapy in the form of generation of functional pancreatic islets from human pluripotent stem cells (hPSCs) and induced pluripotent stem cells (hiPSCs) can provide alternative sources of islet cells for those with type 1 diabetes (T1D). However, these cells would still need to evade the autoimmune process of T1D. In this review, the authors discuss recent and current approaches of generating functional human stem cell–derived islet cells, finding ways to protect these cells from autoimmune rejection, and the limitations of these approaches.Results In vitro, hPSCs successfully differentiate into pancreatic progenitors (PPs) and β-like cells via differentiation protocols that regulate stage-specific pathways. The pathways leading to in vivo functional maturation of hPSC-derived PP have not been fully elucidated yet. Use of more functionally matured hPSC-derived β cell–enriched clusters or islets may offer less variation in efficacy for diabetic patients. It is still undecided if hPSC-derived PPs or fully mature β cells are the better source for transplantation. Studies have also investigated different techniques of encapsulation of transplanted islets to protect grafts from the host immune system, including hPSC-derived β cells encapsulated with triazole-thiomorpholine dioxide and CXCL12-containing sodium alginate–encapsulated hPSC-derived β cells. Preconditioning prior to transplant via pathways to decrease proinflammatory cytokine release, reactive oxygen species (ROS) and inflammatory T-cell infiltration and increasing Tregs can also optimize graft survival.Although hiPSCs derived from adult tissues (such as fibroblast) can be differentiated into pancreatic islet β cells and transplanted autologously, autologous hiPSC production is expensive and time-consuming. Researchers have generated a bank of stringently selected HLA (human leukocyte antigen)-homozygous hiPSC lines, which can be differentiated and transplanted to a broad group of patients. Using this strategy, healthy donors with homozygous HLA-A, HLA-B, and HLA-DR have been selected and, according to the frequent HLA haplotypes in the population, hiPSCs have been selectively generated and preserved via cryopreservation. Although this approach may be effective in populations with less diversity, a large-scale bank will be needed to cover the entire global population. Additionally, transplanted hiPSC-derived insulin-producing cells would need to be protected from the hyperactive immune environment in T1D. Thus, the development of a universal hPSC population that evades immune detection is a major goal of T1D translational research. Induction of programmed death ligand 1 (PD-L1) and other immune tolerance-aiding protein induction presents an innovative approach to improving pancreatic islet graft longevity.ConclusionImmune-evasive human islets derived from hPSCs represent a promising and renewable cell source with a reduced risk of chronic immune suppression to treat T1D.CommentsGeneration of universal hPSC-derived human pancreatic islets and immune tolerance induction will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. Improvements in immune protection, especially encapsulation biomaterials, T-cell or hPSC engineering, preconditioning, and immune tolerance induction will strongly impact the long-term efficacy of islet cell therapy in T1D.An Autoimmune Stem-Like CD8 T Cell Population Drives Type 1 DiabetesGearty SV1,2, Dündar F3,4, Zumbo P3,4, Espinosa-Carrasco G1, Shakiba M1, Sanchez-Rivera FJ5, Socci ND6, Trivedi P1, Lowe SW5, Lauer P7, Mohibullah N8, Viale A8, DiLorenzo TP9,10,11, Betel D4,12,13, Schietinger A1,21Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY; 2Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY; 3Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY; 4Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY; 5Cancer Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY; 6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY; 7Aduro Biotech, Berkeley, CA; 8Integrated Genomics Operation Core, Memorial Sloan Kettering Cancer Center, New York, NY; 9Department of Microbiology and Immunology & Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York, NY; 10Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY; 11The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, NY; 12Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY; 13Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NYNature 2022;602(7895): 156–161BackgroundPrevious studies have revealed that specific CD8 T cells that recognize the β-cell protein islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) represent a major pathogenic population involved in the pathogenesis of type 1 diabetes (T1D) in mice and humans. Some of these studies have also revealed that IGRP-specific CD8 T cells (IGRP T cells) are found in the pancreatic draining lymph node (pLN) and pancreas as early as 5 weeks in non-obese diabetic (NOD) mice. By the time the NOD mice develop diabetes, these CD8 T cells peak in frequency in both pLN and the pancreas. The authors of this study attempted to follow the fate of these IGRP T cells over the entire course of T1D in NOD mice (5–30 weeks).MethodsNOD mice were used for this study. Mice were monitored for diabetes at least weekly and were considered diabetic after two consecutive blood glucose measurements of >250 mg/dL. NOD mice between 15 and 25 weeks were used for phenotypic characterizations of CD8 T cells. T cell isolation, RNA sequencing analysis of CD8 T cells, and clonal analysis were carried out to study the CD8 T cells.ResultsThe pLN IGRP T cells expressed moderate levels of TOX, a driver of CD8 T cell exhaustion in tumor cells and chronic infection, while the pancreatic IGRP T cells expressed low levels of TOX. TCF1, a transcription factor critical for T cell memory, longevity, and self-renewal, is also a target of the Wnt signaling pathway and maintains self-renewal and stemness in adult tissue stem cells. Eighty percent of pLN IGRP T cells were TCF1hi (20% were TCF1lo cells) and were present from 5 weeks of age. On the other hand, pancreatic IGRP T cells had low expression of TCF1 but were transcriptionally different from pLN TCF1lo cells. In addition to pancreatic IGRP-specific CD8T cells (IGRP T cells), CD8 T cells specific to other β cells also had a TCF1lo and CD39hiPD1hi phenotype in the pancreas. Phenotypic bifurcation in the pLN (TCF1hi and TCF1lo) thus appears to play a key role in the β cell–specific CD8 T cell repertoire: pLNTCF1hi, pLNTCF1lo, and pancreatic TCFlo cells. The pLNTCFhi cells, which self-renew, form pancreatic TCFlo autoimmune mediators (CD8 T cells) that destroy β cells.ConclusionSpecific CD8 T cells that recognize the β-cell protein IGRP represent a major population involved in the pathogenesis of T1D.CommentsThe authors have commented on the possibility of finding newer pathways for T1D therapies by targeting stem cell–like progenitor cells, which are a source of pathogenic autoimmune cells, as well as targeting the pathways of generation and entry of these cells in the pancreas. As an example, fingolimod, currently used in the treatment of multiple sclerosis, may be indicated in T1D. The drug suppresses the exit of lymphocytes from lymph nodes and possibly entry into the pancreas. We await future studies.Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes PathogenesisToren E1,2, Burnette KS2,3, Banerjee R4, Hunter CS1,2, Tse HM2,31Department of Medicine, Division of Endocrinology Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL; 2Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL; 3Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL; 4Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MDFront Immunol 2021;12: 756548BackgroundMultiple studies have revealed that, due to its inherent properties, the β cell may be contributing to the pathogenesis of type 1 diabetes (T1D) and is, therefore, more than a passive target. To maintain euglycemia, β cells must respond rapidly and appropriately in a tightly controlled manner, requiring multiple metabolic pathways. Additionally, β cells are highly vascularized and have reduced antioxidant defense mechanisms, which make them sensitive to proinflammatory and autoimmune-mediated destructive pathways. The authors have reviewed properties of the β cell that indicate its complicit role in the autoimmune disease process.ResultsUnder the action of calcium, β cells secrete multiple hormones as protein granules with the endoplasmic reticulum (ER) as the site of protein production and folding. When there is increased demand of insulin secretion, the protein folding capacity of the ER may be exceeded, leading to misfolded proteins. This leads to a stressed environment in the ER, and subsequent degradation of insulin secretory granule proteins. This, in turn, leads to production of neoantigens, which can trigger islet autoimmunity, insulitis, and increased permeability. The dense vasculature of the islet cells facilitates an open environment where immune cells from local and distant sites have easy access, further worsening the proinflammatory condition.Interestingly, subpopulations of β cells have been identified: B1-B4, first responder cells, hub or pacemaker cells, and virgin cells, which are incapable of glucose sensing. Although the relationship between these cell subtypes is still under investigation, β cell heterogeneity may also have a role in T1D pathogenesis, with some cells more prone to ER stress and, thus, more likely to trigger autoimmunity.Conclusionβ Cells display an increased vulnerability to destruction and can also perpetuate inflammatory and autoimmune responses in a destructive positive feedback loop. Manipulation of ER function and other oxidative stress pathways may provide new strategies for T1D treatment, including stem cell therapy.CommentsT1D intervention studies in recent years have focused solely on modulating the immune responses affecting β cell function. However, newer agents that can modulate ER dysfunction and oxidative pathways, as well as a better understanding of the β cell subpopulation and its exploitation, may provide one of the strongest clues in the pathway to T1D prevention and treatment.Author Disclosure StatementThe authors declare that they have no conflicts of interest related to this article.References1. Xu G, Chen J, Jing G, Shalev A. Preventing b-Cell Loss and Diabetes With Calcium Channel Blockers cell loss and diabetes with calcium channel blockers. Diabetes 2012;61: 848–856. Crossref, Medline, Google Scholar2. Ovalle F, Grimes T, Xu G, et al. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nat Med 2018;24: 1108–1112. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 25Issue S1Feb 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Bimota Nambam, Nataša Bratina, and Desmond Schatz.Immune Intervention and Replacement Therapies in Type 1 Diabetes.Diabetes Technology & Therapeutics.Feb 2023.S-201-S-206.http://doi.org/10.1089/dia.2023.2513Published in Volume: 25 Issue S1: February 20, 2023PDF download