Relevant Publications

Autoimmune Disease

  • Song et al. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther. 2024 Oct 4;9(1):263. doi: 10.1038/s41392-024-01952-8.
  • National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. https://doi.org/10.17226/26554.

Regulatory T cells (Tregs)

Review articles

  • Wardell et al. Harnessing the biology of regulatory T cells to treat disease. Nat Rev Drug Discov. 2024 Dec 16. doi: 10.1038/s41573-024-01089-x.
  • Bittner et al. Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond. Trends Immunol. 2023 Jun;44(6):468-483. doi: 10.1016/j.it.2023.04.005.
  • Raffin et al. Treg cell-based therapies: challenges and perspectives. Nat Rev Immunol. 2020 Mar;20(3):158-172. doi: 10.1038/s41577-019-0232-6.
  • Sakaguchi et al. Regulatory T Cells and Human Disease. Annu Rev Immunol. 2020. 38:541–66. https://doi.org/10.1146/annurev-immunol-042718-041717.
  • Muñoz-Rojas et al. Tissue regulatory T cells: regulatory chameleons. Nat Rev Immunol. 2021 Sep;21(9):597-611. doi: 10.1038/s41577-021-00519-w.

Treg biology

  • Miyao et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012 Feb 24;36(2):262-75.
  • Rubtsov et al. Stability of the regulatory T cell lineage in vivo. Science. 2010 Sep 24;329(5999):1667-71. doi: 10.1126/science.1191996.
  • Hori. FOXP3 as a master regulator of Treg cells. Nat Rev Immunol. 2021 Oct;21(10):618-619. doi: 10.1038/s41577-021-00598-9.
  • Liu et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006 Jul 10;203(7):1701-11. doi: 10.1084/jem.20060772.

Clinical experience with Treg therapies

  • Guinan et al. Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial. Am J Transplant. 2023 Dec;23(12):1872-1881. doi: 10.1016/j.ajt.2023.06.012.
  • Bluestone et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134.
  • Hepatology. 80(S1):S1-S2011, October 2024 (https://journals.lww.com/hep/toc/2024/10001). Abstract #1386, The safety and tolerability of QEL-001, an autologous chimeric antigen receptor (CAR) T regulatory (Treg) cell therapy, in liver transplantation – a safety cohort in the LIBERATE study.
  • Chandran et al. Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants. Am J Transplant. 2017 Nov;17(11):2945-2954. doi: 10.1111/ajt.14415.
  • Chwojnicki et al. Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study. BioDrugs. 2021 Jan;35(1):47-60. doi: 10.1007/s40259-020-00462-7.
  • Harden et al. Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients. Am J Transplant. 2021 Apr;21(4):1603-1611. doi: 10.1111/ajt.16395.
  • Sánchez-Fueyo et al. Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. 2020 Apr;20(4):1125-1136. doi: 10.1111/ajt.15700.
  • Dall’Era et al. Adoptive Treg Cell Therapy in a Patient With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019 Mar;71(3):431-440. doi: 10.1002/art.40737.
  • Di Ianni et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011 Apr 7;117(14):3921-8. doi: 10.1182/blood-2010-10-311894.
  • Bender et al. A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. Sci Transl Med. 2024 May 8;16(746):eadn2404. doi: 10.1126/scitranslmed.adn2404.
  • Sawitzki et al., Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet. 2020 May 23;395(10237):1627-1639. doi: 10.1016/S0140-6736(20)30167-7.
  • Mathew et al. A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants. Sci Rep. 2018 May 9;8(1):7428. doi: 10.1038/s41598-018-25574-7.
  • Dong et al. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021 Sep 22;6(18):e147474. doi: 10.1172/jci.insight.147474.
  • Todo et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. 2016 Aug;64(2):632-43. doi: 10.1002/hep.28459.
  • Desreumaux et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012 Nov;143(5):1207-1217.e2. doi: 10.1053/j.gastro.2012.07.116.
  • Tang et al. Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans. Sci Transl Med. 2022 Nov 2;14(669):eabo2628. doi: 10.1126/scitranslmed.abo2628.
  • Brunstein et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016 Feb 25;127(8):1044-51. doi: 10.1182/blood-2015-06-653667.

Multiple Sclerosis

Pathophysiology

  • Lassmann. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019 Jan 10;9:3116. doi: 10.3389/fimmu.2018.03116.
  • Absinta et al. Mechanisms underlying progression in multiple sclerosis. Curr Opin Neurol. 2020 Jun;33(3):277-285. doi: 10.1097/WCO.0000000000000818.
  • Ransohoff. Multiple sclerosis: role of meningeal lymphoid aggregates in progression independent of relapse activity. Trends Immunol. 2023 Apr;44(4):266-275. doi: 10.1016/j.it.2023.02.002.
  • Howell et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011 Sep;134(Pt 9):2755-71. doi: 10.1093/brain/awr182.
  • Luchetti et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018 Apr;135(4):511-528. doi: 10.1007/s00401-018-1818-y.
  • Ahmed et al. Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis. JCI Insight. 2022 Mar 8;7(5):e151683. doi: 10.1172/jci.insight.151683.
  • Absinta et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature. 2021 Sep;597(7878):709-714. doi: 10.1038/s41586-021-03892-7.
  • Absinta et al. Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions. J Clin Invest. 2016 Jul 1;126(7):2597-609. doi: 10.1172/JCI86198.
  • Absinta et al. Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo. JAMA Neurol. 2019 Dec 1;76(12):1474-1483. doi: 10.1001/jamaneurol.2019.2399.
  • Cagol et al. Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS. Neurology. 2024 Jan 9;102(1):e207768. doi: 10.1212/WNL.0000000000207768.
  • Reeves et al. Paramagnetic rim lesions predict greater long-term relapse rates and clinical progression over 10 years. Mult Scler. 2024 Apr;30(4-5):535-545. doi: 10.1177/13524585241229956.
  • Reeves JA et al. Associations Between Paramagnetic Rim Lesion Evolution and Clinical and Radiologic Disease Progression in Persons With Multiple Sclerosis. Neurology. 2024 Nov 26;103(10):e210004. doi: 10.1212/WNL.0000000000210004.
  • George et al. Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies. Neurol Genet. 2016 Aug 4;2(4):e87. doi: 10.1212/NXG.0000000000000087.
  • Schmidt et al. HLA-DR15 haplotype and multiple sclerosis: a HuGE review. Am J Epidemiol. 2007 May 15;165(10):1097-109. doi: 10.1093/aje/kwk118.
  • Jahn et al. Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol. 2009 Aug;40(1):55-72. doi: 10.1007/s12035-009-8071-2.
  • Ota et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990 Jul 12;346(6280):183-7. doi: 10.1038/346183a0.
  • Ransohoff et al. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012 Sep;12(9):623-35. doi: 10.1038/nri3265.

Clinical

  • Hittle et al. Population-Based Estimates for the Prevalence of Multiple Sclerosis in the United States by Race, Ethnicity, Age, Sex, and Geographic Region. JAMA Neurol. 2023 Jul 1;80(7):693-701. doi: 10.1001/jamaneurol.2023.1135.
  • Kappos et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020 Sep 1;77(9):1132-1140. doi: 10.1001/jamaneurol.2020.1568.
  • Tur et al. Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis. JAMA Neurol. 2023 Feb 1;80(2):151-160. doi: 10.1001/jamaneurol.2022.4655.
  • Confavreux et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000 Nov 16;343(20):1430-8. doi: 10.1056/NEJM200011163432001.
  • Weinshenker et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989 Dec;112 (Pt 6):1419-28. doi: 10.1093/brain/112.6.1419.
  • Capanna et al. Is the effect of drugs in progressive MS only due to an effect on inflammation? A subgroup meta-analysis of randomised trials. Mult Scler. 2022 Oct;28(11):1744-1751. doi: 10.1177/13524585221094944.
  • Maggi et al. B cell depletion therapy does not resolve chronic active multiple sclerosis lesions. EBioMedicine. 2023 Aug;94:104701.
  • Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588. Erratum in: JAMA. 2020 Apr 7;323(13):1318. doi: 10.1001/jama.2020.2604.
  • Kappos et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6.
  • Tolebrutinib ECTRIMS presentation #O136 2024-09-20: Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results From the Phase 3 HERCULES Trial, https://congress.sanofimedical.com/ectrims-2024/neurology/tolebrutinib-in-multiple-sclerosis/7671/7670.
  • Blazier et al., Evaluating Large Scale Proteomic Changes in Cerebrospinal Fluid of Multiple Sclerosis Patients Treated with Tolebrutinib. 8th Annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum; San Diego, CA, USA; 23–25 February 2023. P019.
  • Bar-Or A et al. Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials. EBioMedicine. 2023 Jul;93:104662. doi: 10.1016/j.ebiom.2023.104662.

Preclinical

  • Malviya et al. Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells. J Autoimmun. 2020 Mar;108:102401. doi: 10.1016/j.jaut.2020.102401.
  • Kieback et al. Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity. 2016 May 17;44(5):1114-26. doi: 10.1016/j.immuni.2016.04.018.
  • Kim et al. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J Autoimmun. 2018 Aug;92:77-86. doi: 10.1016/j.jaut.2018.05.003.
  • Wilkinson et al. Partial CD25 Antagonism Enables Dominance of Antigen-Inducible CD25high FOXP3+ Regulatory T Cells As a Basis for a Regulatory T Cell-Based Adoptive Immunotherapy. Front Immunol. 2017 Dec 14;8:1782. doi: 10.3389/fimmu.2017.01782.
  • Pohar et al. Antigen receptor-engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice. Eur J Immunol. 2022 Aug;52(8):1335-1349. doi: 10.1002/eji.202249845.
  • Dombrowski et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci. 2017 May;20(5):674-680. doi: 10.1038/nn.4528.
  • Ito et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature. 2019 Jan;565(7738):246-250. doi: 10.1038/s41586-018-0824-5.
  • Hamaguchi et al. Circulating transforming growth factor-β1 facilitates remyelination in the adult central nervous system. Elife. 2019 May 9;8:e41869. doi: 10.7554/eLife.41869.

Type 1 Diabetes

Pathophysiology

  • Herold et al. The immunology of type 1 diabetes. Nat Rev Immunol. 2024 Jun;24(6):435-451. doi: 10.1038/s41577-023-00985-4.
  • Zhao et al. The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes. EBioMedicine. 2021 Jul;69:103431. doi: 10.1016/j.ebiom.2021.103431.
  • Mitchell et al. Temporal development of T cell receptor repertoires during childhood in health and disease. JCI Insight. 2022 Sep 22;7(18):e161885. doi: 10.1172/jci.insight.161885.

Clinical

  • Gregory et al. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol. 2022 Oct;10(10):741-760. doi: 10.1016/S2213-8587(22)00218-2.
  • Dayan et al. Changing the landscape for type 1 diabetes: the first step to prevention. Lancet. 2019 Oct 5;394(10205):1286-1296. doi: 10.1016/S0140-6736(19)32127-0.
  • Lam et al. A little help from residual β cells has long-lasting clinical benefits. J Clin Invest. 2021 Feb 1;131(3):e143683. doi: 10.1172/JCI143683.
  • Rogers et al. Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. BMC Med. 2017 Nov 8;15(1):199. doi: 10.1186/s12916-017-0958-6.
  • Dabelea et al. Twenty years of pediatric diabetes surveillance: what do we know and why it matters. Ann N Y Acad Sci. 2021 Jul;1495(1):99-120. doi: 10.1111/nyas.14573.
  • Tuomilehto et al. Update on Worldwide Trends in Occurrence of Childhood Type 1 Diabetes in 2020. Pediatr Endocrinol Rev. 2020 Mar;17(Suppl 1):198-209. doi: 10.17458/per.vol17.2020.tol.epidemiologychildtype1diabetes.
  • Foster et al. State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther. 2019 Feb;21(2):66-72. doi: 10.1089/dia.2018.0384.
  • Herold et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226.
  • Sims et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021 Mar 3;13(583):eabc8980. doi: 10.1126/scitranslmed.abc8980.
  • Hirsch. FDA approves teplizumab: a milestone in type 1 diabetes. Lancet Diabetes Endocrinol. 2023 Jan;11(1):18. doi: 10.1016/S2213-8587(22)00351-5.
  • Bluestone et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189.
  • Bender et al. A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. Sci Transl Med. 2024 May 8;16(746):eadn2404. doi: 10.1126/scitranslmed.adn2404.
  • Marek-Trzonkowska et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up. Clin Immunol. 2014 Jul;153(1):23-30. doi: 10.1016/j.clim.2014.03.016.
  • Zieliński et al. Combined therapy with CD4+ CD25highCD127- T regulatory cells and anti-CD20 antibody in recent-onset type 1 diabetes is superior to monotherapy: Randomized phase I/II trial. Diabetes Obes Metab. 2022 Aug;24(8):1534-1543. doi: 10.1111/dom.14723.
  • Bettini et al. Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes. Diabetes. 2021 Jun;70(6):1211-1219. doi: 10.2337/dbi18-0058.
  • Herold et al. Teplizumab: A Disease-Modifying Therapy for Type 1 Diabetes That Preserves β-Cell Function. Diabetes Care. 2023 Oct 1;46(10):1848-1856. doi: 10.2337/dc23-0675.

Preclinical

  • Tang et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004 Jun 7;199(11):1455-65. doi: 10.1084/jem.20040139.
  • Yang et al. Pancreatic islet-specific engineered Tregs exhibit robust antigen-specific and bystander immune suppression in type 1 diabetes models. Sci Transl Med. 2022 Oct 5;14(665):eabn1716. doi: 10.1126/scitranslmed.abn1716.
  • Tarbell et al. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med. 2004 Jun 7;199(11):1467-77. doi: 10.1084/jem.20040180.