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Cited by 377Diabetes and associated disordersT-cell and B-cell ImmunologyPancreatic function and diabetes

Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals

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Sims, Emily K., Bundy, Brian N., Stier, Kenneth, Serti, Elisavet, Lim, Noha, Long, S. Alice, Geyer, Susan M., Moran, Antoinette +15 more·2021·Science Translational Medicine
DOI 10.1126/scitranslmed.abc8980PMC PMC8610022
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Abstract

Teplizumab treatment of nondiabetic relatives at high risk for T1D induces partially exhausted CD8 + T cells and improves beta cell function.

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  • Anti-CD3 treatment (teplizumab) has been shown to induce long-term protection (currently up to six years) from T1D in at-risk individuals.

    “Moreover, anti-CD3 treatment (teplizumab) has been shown to induce long-term protection (currently up to six years) from T1D in at-risk individuals, but the mechanisms responsible for this long-term protection remain incompletely understood29,30”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [30]

    The Results section reports a sustained delay in T1D among high-risk relatives treated with teplizumab; eight treated participants followed beyond five years remained undiagnosed. It does not establish protection specifically through six years, and describes delayed diagnosis rather than permanent prevention. Page numbers were not provided in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Follow-up after completion of the trial showed an extension of the delay to a median of 32 months.

    “Followup after completion of the trial showed an extension of the delay to a median of 32 months.43”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [43]

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References 65 · Cited by 377

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  1. [2]Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, Greenbaum CJ, Herold KC, Krischer JP, Lernmark A, Ratner RE, Rewers MJ, Schatz DA, Skyler JS, Sosenko JM, Ziegler AG, Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes care 38, 1964– 1974 (2015). 26404926 PMC5321245
  2. [3]Krischer JP, Lynch KF, Lernmark A, Hagopian WA, Rewers MJ, She JX, Toppari J, Ziegler AG, Akolkar B, T. S. Group, Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study. Diabetes care 40, 1194– 1202 (2017). 28646072 PMC5566280
  3. [4]Mahon JL, Sosenko JM, Rafkin-Mervis L, Krause-Steinrauf H, Lachin JM, Thompson C, Bingley PJ, Bonifacio E, Palmer JP, Eisenbarth GS, Wolfsdorf J, Skyler JS, C. TrialNet Natural History, G. Type 1 Diabetes TrialNet Study, The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results. Pediatric diabetes 10, 97– 104 (2009). 18823409
  4. [5]Siljander HT, Hermann R, Hekkala A, Lahde J, Tanner L, Keskinen P, Ilonen J, Simell O, Veijola R, Knip M, Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced beta-cell autoimmunity. Eur J Endocrinol 169, 479– 485 (2013). 23904276
  5. [6]Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, Maahs DM, Tamborlane WV, Bergenstal R, Smith E, Olson BA, Garg SK, State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther 21, 66– 72 (2019). 30657336 PMC7061293
  6. [11]Sims EK, DiMeglio LA, Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes. Mol Metab 27S, S129– S138 (2019). 31500824 PMC6768572
  7. [12]Koskinen MK, Helminen O, Matomäki J, Aspholm S, Mykkänen J, Mäkinen M, Simell V, Vähä-Mäkilä M, Simell T, Ilonen J, Reduced β-cell function in early preclinical type 1 diabetes. European Journal of Endocrinology 174, 251– 259 (2016). 26620391 PMC4712442
  8. [13]Bingley PJ, Wherrett DK, Shultz A, Rafkin LE, Atkinson MA, Greenbaum CJ, Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes. Diabetes Care 41, 653– 661 (2018). 29559451 PMC5860837
  9. [14]Greenbaum CJ, Speake C, Krischer J, Buckner J, Gottlieb PA, Schatz DA, Herold KC, Atkinson MA, Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes-The TrialNet Experience. Diabetes 67, 1216– 1225 (2018). 29769238 PMC6014559
  10. [15]Nathan BM, Boulware D, Geyer S, Atkinson MA, Colman P, Goland R, Russell W, Wentworth JM, Wilson DM, Evans-Molina C, Wherrett D, Skyler JS, Moran A, Sosenko JM, T. Type 1 Diabetes, G. Diabetes Prevention Trial-Type 1 Study, Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials. Diabetes care 40, 1494– 1499 (2017). 28860125 PMC5652585
  11. [16]Sosenko JM, Palmer JP, Rafkin-Mervis L, Krischer JP, Cuthbertson D, Mahon J, Greenbaum CJ, Cowie CC, Skyler JS, G. Diabetes Prevention Trial-Type 1 Study, Incident dysglycemia and progression to type 1 diabetes among participants in the Diabetes Prevention Trial-Type 1. Diabetes care 32, 1603– 1607 (2009). 19487644 PMC2732147
  12. [17]Palmer JP, C-peptide in the natural history of type 1 diabetes. Diabetes Metab Res Rev 25, 325– 328 (2009). 19267337 PMC2895504
  13. [19]Hagopian W, Ferry RJ Jr., Sherry N, Carlin D, Bonvini E, Johnson S, Stein KE, Koenig S, Daifotis AG, Herold KC, Ludvigsson J, I. Protege Trial, Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protege trial. Diabetes 62, 3901– 3908 (2013). 23801579 PMC3806608
  14. [20]Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, Boyle KD, Keyes-Elstein L, Aggarwal S, Phippard D, Sayre PH, McNamara J, Bluestone JA, A. T. E. S. T. Ab, Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 62, 3766– 3774 (2013). 23835333 PMC3806618
  15. [21]Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA, Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346, 1692– 1698. (2002). 12037148
  16. [22]Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L, Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352, 2598– 2608 (2005). 15972866
  17. [23]Long SA, Thorpe J, DeBerg HA, Gersuk V, Eddy J, Harris KM, Ehlers M, Herold KC, Nepom GT, Linsley PS, Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes. Sci Immunol 1, (2016). PMC5486405 28664195
  18. [24]Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ Jr., Bode B, Aronoff S, Holland C, Carlin D, King KL, Wilder RL, Pillemer S, Bonvini E, Johnson S, Stein KE, Koenig S, Herold KC, Daifotis AG, I. Protege Trial, Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 378, 487– 497 (2011). 21719095 PMC3191495
  19. [25]Tooley JE, Vudattu N, Choi J, Cotsapas C, Devine L, Raddassi K, Ehlers MR, McNamara JG, Harris KM, Kanaparthi S, Phippard D, Herold KC, Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 46, 230– 241 (2016). 26518356 PMC4882099
  20. [28]G. Diabetes Prevention Trial--Type 1 Diabetes Study, Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346, 1685– 1691 (2002). 12037147
  21. [29]G. Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study, Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ, Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. JAMA: the journal of the American Medical Association 318, 1891– 1902 (2017). 29164254 PMC5798455
  22. [30]Elding Larsson H, Lundgren M, Jonsdottir B, Cuthbertson D, Krischer J, A.-I. T. S. G. Di, Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial. Pediatric diabetes 19, 410– 419 (2018). 29171140
  23. [31]Gale EA, Bingley PJ, Emmett CL, Collier T, G. European Nicotinamide Diabetes Intervention Trial, European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 363, 925– 931 (2004). 15043959
  24. [32]Eizirik DL, Colli ML, Ortis F, The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5, 219– 226 (2009). 19352320
  25. [33]Tsai EB, Sherry NA, Palmer JP, Herold KC, The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 49, 261– 270 (2006). 16404554
  26. [35]Herold KC, Usmani-Brown S, Ghazi T, Lebastchi J, Beam CA, Bellin MD, Ledizet M, Sosenko JM, Krischer JP, Palmer JP, G. Type 1 Diabetes TrialNet Study, beta cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest 125, 1163– 1173 (2015). 25642774 PMC4362259
  27. [36]Sherry NA, Tsai EB, Herold KC, Natural history of beta-cell function in type 1 diabetes. Diabetes 54 Suppl 2, S32– 39 (2005). 16306337
  28. [37]Sims EK, Evans-Molina C, Tersey SA, Eizirik DL, Mirmira RG, Biomarkers of islet beta cell stress and death in type 1 diabetes. Diabetologia, (2018). PMC6160346 30112687
  29. [38]Herold KC, Bucktrout SL, Wang X, Bode BW, Gitelman SE, Gottlieb PA, Hughes J, Joh T, McGill JB, Pettus JH, Potluri S, Schatz D, Shannon M, Udata C, Wong G, Levisetti M, Ganguly BJ, Garzone PD, R. N. W. Group, Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes. JCI Insight 4, (2019). PMC6975260 31852846
  30. [39]Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA, A Single Course of Anti-CD3 Monoclonal Antibody hOKT3{gamma}1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes. Diabetes 54, 1763– 1769 (2005). 15919798 PMC5315015
  31. [40]McLane LM, Abdel-Hakeem MS, Wherry EJ, CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol 37, 457– 495 (2019). 30676822
  32. [41]Sosenko JM, Palmer JP, Greenbaum CJ, Mahon J, Cowie C, Krischer JP, Chase HP, White NH, Buckingham B, Herold KC, Cuthbertson D, Skyler JS, Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes care 29, 643– 649 (2006). 16505520
  33. [43]Chatenoud L, Primo J, Bach JF, CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158, 2947– 2954 (1997). 9058834
  34. [44]Akirav EM, Baquero MT, Opare-Addo LW, Akirav M, Galvan E, Kushner JA, Rimm DL, Herold KC, Glucose and inflammation control islet vascular density and beta-cell function in NOD mice: control of islet vasculature and vascular endothelial growth factor by glucose. Diabetes 60, 876– 883 (2011). 21307078 PMC3046848
  35. [45]Sherry NA, Kushner JA, Glandt M, Kitamura T, Brillantes AM, Herold KC, Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55, 3238– 3245 (2006). 17130466
  36. [46]Perdigoto AL, Preston-Hurlburt P, Clark P, Long SA, Linsley PS, Harris KM, Gitelman SE, Greenbaum CJ, Gottlieb PA, Hagopian W, Woodwyk A, Dziura J, Herold KC, N. Immune Tolerance, Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis. Diabetologia 62, 655– 664 (2019). 30569273 PMC6402971
  37. [47]Herold KC, Gitelman SE, Willi SM, Gottlieb PA, Waldron-Lynch F, Devine L, Sherr J, Rosenthal SM, Adi S, Jalaludin MY, Michels AW, Dziura J, Bluestone JA, Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia 56, 391– 400 (2013). 23086558 PMC3537871
  38. [48]Battaglia M, Anderson MS, Buckner JH, Geyer SM, Gottlieb PA, Kay TWH, Lernmark A, Muller S, Pugliese A, Roep BO, Greenbaum CJ, Peakman M, Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetologia 60, 2139– 2147 (2017). 28770323 PMC5838353
  39. [49]Rana S, Yue S, Stadel D, Zoller M, Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 44, 1574– 1584 (2012). 22728313
  40. [50]A. American Diabetes, 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care 42, S13– S28 (2019). 30559228
  41. [51]Sims EK, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F, Perkins SM, Mirmira RG, Sosenko J, DiMeglio LA, Evans-Molina C, Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes care 39, 1519– 1526 (2016). 27385327 PMC5001142
  42. [52]Allison DB, Paultre F, Maggio C, Mezzitis N, Pi-Sunyer FX, The use of areas under curves in diabetes research. Diabetes Care 18, 245– 250 (1995). 7729306
  43. [53]Steele C, Hagopian WA, Gitelman S, Masharani U, Cavaghan M, Rother KI, Donaldson D, Harlan DM, Bluestone J, Herold KC, Insulin secretion in type 1 diabetes. Diabetes 53, 426– 433 (2004). 14747294
  44. [54]Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B, Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest 77, 98– 105 (1986). 3511094 PMC423314
  45. [55]Van Cauter E, Mestrez F, Sturis J, Polonsky KS, Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 41, 368– 377 (1992). 1551497
  46. [56]Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS, Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82, 524– 530 (1997). 9024248
  47. [57]Ghazi T, Rink L, Sherr JL, Herold KC, Acute metabolic effects of exenatide in patients with type 1 diabetes with and without residual insulin to oral and intravenous glucose challenges. Diabetes Care 37, 210– 216 (2014). 23939544 PMC3968447
  48. [58]Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter E, Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 318, 1231– 1239 (1988). 3283554
  49. [59]Long SA, Thorpe J, Herold KC, Ehlers M, Sanda S, Lim N, Linsley PS, Nepom GT, Harris KM, Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes. Cell Immunol 319, 3– 9 (2017). 28844471 PMC5614459

Authors
Sims, E. K., Bundy, B. N., Stier, K., Serti, E., Lim, N., Long, S. A., Geyer, S. M., Moran, A., Greenbaum, C. J., Evans-Molina, C., Herold, K. C., Type 1 Diabetes TrialNet Study Group, DiMeglio, L. A., Gitelman, S. E., Gottlieb, P. A., Marks, J. B., Moore, W., Rodriguez, H., Russell, W. E., Schatz, D., Tsalikian, E., Wherrett, D. K., & Ziegler, A.-G.
Affiliations
  • Indiana University School of Medicine (US)
  • University of South Florida (US)
  • Yale University (US)
  • Immune Tolerance Network (US)
  • Benaroya Research Institute (US)
  • Mayo Clinic (US)
  • University of Minnesota (US)
  • Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Corresponding author
Herold, Kevan C.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-03-03
Volume
13
Issue
583
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abc8980
PMC
PMC8610022
OpenAlex
W3133678581
Cited by
377
References
65
Citations by year
2026: 65 · 2025: 94 · 2024: 78 · 2023: 69 · 2022: 41 · 2021: 30
FWCI
30.66
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • National Institutes of Health (U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085453, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, UC4 DK11700901, U01 DK 106693-02, UM1AI109565, UM1AI109565)
  • Juvenile Diabetes Research Foundation International
  • JDRF (U01 DK061034, U01 DK085466, U01 DK085476, U01 DK107014, UC4 DK11700901, 106693, 2019-833-S-B)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
teplizumab, type 1 diabetes prevention, beta-cell function, T cell exhaustion, T cell subsets, immunotherapy, metabolic response
MeSH terms
C-Peptide, Diabetes Mellitus, Type 1, Humans, Insulin, CD8-Positive T-Lymphocytes, Antibodies, Monoclonal, Humanized

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