1型糖尿病の完治にむけて

//Background//---
 Type 2 diabetes shows insulin resistance, therefore insulin itself is secreted and less-effective. On the other hand, type 1 diabetes is lack of insulin secretion due to β-cell disfunction/death by immune activation, so type-1 diabetes is autoimmune disease. β-cell in pancreas islet is destroyed by aberrant T cell. The causes of type 1 diabetes remain elusive, although several risk factors including HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are assumed. This is pediatric-onset disease, whose median age of diagnosis is about 12 years(1). Epidemiologically, 10-20 children per 100,000 in the United States, Southern Europe, and 1-3 children per 100,000 in much of Asia are affected with type-1 diabetes. The number of pancreatic β-cell becomes peak from 0 years to 2 years , then gradually decreases until 12 years, at which almost 80% of β-cell is destroyed (See Ref.(1) Fig.1). The risk of type 1 diabetes could be emerged from utero. The risk factor is complex including inheritable character, environmental factor (hygiene hypothesis, infection, food allergy, industrialization, intestinal microbiota-dysbiosis)(2). Typical insulin therapy cannot change the underlying disease or/and fully prevent complication including diabetic ketoacidosis, severe hypoglycemia, long-term vascular complication, cardiovascular disease, nephropathy, neuropathy, retinopathy(6).
 
//Typical clinical symptom//---
*Weight loss
*Polydipsia (extreme thirst)
*Polyuria (excessive urination)
 
//Biomarkers//---
>90% of children with T1D have autoantibodies to at least one islet-specific autoantibodies, whose volume is dependent on disease stage progression(1,4), so early diagnosis could be possible via biomarkers.
*Antibodies to insulin (IAA)(2,3)
*Glutamate decarboxylase (GADA)(2,3)
*Islet specific zinc transporter (ZnT8A)(2,3)
 
//Immunotherapy((1), See Table.1)//---
Type 1 diabetes is immune related disease, so immunotherapy is one of the mainstays for the treatment. However, objective age range is relatively high compared to the timing of disease onset. On timing of immunotherapy, the time order(from *1 to *3) is as followed.
(*1): Non antigen specific (NAS) immunotherapy
(*2): Sequential/combined NAS immunotherapy
(*3): Antigen specific immunotherapy
The effectiveness of immunotherapy varies in each disease stage. In initial stage with genetic risk, effectiveness may be low due to poor selectivity and progressive stage with destroyed βcell, effectiveness may be also low. On the other hand,  in middle stage with immune inflammation and βcell injury, immune therapy is promising(6).
The candidate of immunotherapy is β-cell antagonists/Treg-friendly therapy/Inhibition of T cell activation/Cytokine antagonist/Promote Teff depletion and exhaustion/βcell regeneration(See Ref.(6) Fig.1). Other possible target may be that antagonist of binding βcell and Teff cell. Verapamil and glp-1 agonist could is the candidate for βcell regeneration.
---
(Current clinical trial)
*Tepizumab, against T cell(CD3), for 8 to 35 years (5)
*ATG, against T cells, for 12 to 45 years, NCT02215200
*Rituximab, against B cells (CD20), for 8 to 40 years NCT00279305
*Abatacept (CTLA4-Ig), against T cell activation, CD80, CD86, for 6 to 45 years, NCT00505375
*Anti-IL-21(NNC0114-0006)(+liraglutide), against IL-21 (T cells, B cells, natural killer cells), for 18 to 45 years, NCT02443155
*Golimumab, against TNF, for 6 to 21 years, NCT03298542
 
//Therapy by microbiome//---
 BCG vaccine, probiotics, coxsackie B vaccine are the candidate for the treatment. However, BCG vaccine shows no robust evidence for the treatment of type1 diabetes(8). Coxsackie B vaccine may prevent coxsackievirus B induced diabetes(9), but general efficacy may be controversial.
 
//Islet β-cell repair//---
 Immune control in type1 diabetes is a prerequisite, but it is not sufficient. Repair of β-cell and tissue in damaged islet needs to be enhanced. Potential enhancers of β-cell are nicotinamide(vitamin-B group), glucose, protein-rich diets, and branched chain amino acids(10), so metabolic approach is one of the candidate for islet β-cell repair.
 On the other hand, macrophage generally play an important role in tissue repair. After beta-cell death, islet macrophage shift to a reparative (regenerative) state and function as efferocytosis.
 
//β-cell replacement therapy//---
 The number of β-cell in pancreas in the patients with type 1 diabetes significantly reduced by 80% compared to peak number, so we need to supply new β-cell (engraftment) or makes it regenerate for the recovery and the complete therapy. To date, successful transplantation of cadaveric islets using the Edmonton protocol demonstrate cell therapy in which inserting mature β-cell into pancreas in the type 1 diabetes patients can succeed and it provides a functional cure(7,17,18). Cadaveric islets is limited, so renewable and off-the-shelf stem cell technology is promising(7).
 Nathaniel J. Hogrebe, Kristina G. Maxwell, Punn Augsornworawat & Jeffrey R. Millman develop a step-by-step methodology(*1~*4) for generating human pluripotent stem cell-derived pancreatic functional βcell that secrete high amounts of insulin in response to glucose stimulation(7)(See Fig.1).
(*1): Endoderm Treatment with Activin A and CHIR99021
(*2): Progenitor cell formation:
Generating PDX1 + /NKX6-1 + pancreatic progenitors through the timed application of keratinocyte growth factor, SANT1, TPPB, LDN193189 and retinoic acid
(*3): Stem cell β-cell formation:
Endocrine induction and subsequent stem cell βcell specification is achieved with a cocktail consisting of the cytoskeletal depolymerizing compound latrunculin A combined with XXI, T3, ALK5 inhibitor II, SANT1 and retinoic acid.
(*4): Islet clusters formation:
Stem cell β-cells and other endocrine cell types can then be aggregated into islet-like clusters for analysis and transplantation.
However, clinical islet transplantation requires lifelong immunosuppressive therapy to prevent immune-mediate graft loss. This graft decreases after transplantation due to immune activation against “foreign compound”(12).
 
//Cell specific delivery system//---
 Both immunotherapy and generation of human pluripotent stem cell-derived pancreatic β-cell in vivo (cell replacement therapy/β-cell regeneration) may be able to be realized in the cell-specific delivery system in a spatiotemporal common fashion . Components necessary to produce pluripotent stem cell derived βcell in pancreas islet, are infused into nanocarrier and β-cell is protected from activate T cell by surface receptor of nanocarrier specific to pancreatic islet β-cell, thereby specific delivery system toward pancreas could be realized simultaneously. In this method, immune activation could be controlled by proper choice of nano-carrier.
 
//Discussion//---
 The fundamental remaining barrier of refractory disease is medically enhanced recovery/repair for the significantly damaged organ/tissue/cell. For example, we can resect the tumor tissue by surgery, but the damaged tissue by cancer cells cannot be repaired in a medically enhanced manner, at least this is difficult. Hence, we cannot completely cure cirrhosis which is extreme liver damage. This can be applied to type-1 diabetes. We need to repair the damaged pancreatic islet, but this is medically difficult without cell/tissue replacement. However, this replacement always entails graft-versus-host reaction and inefficiency of engraftment and retainment of replaced cell/tissue. Therefore, if we can find the innovative way to recover the significant damaged tissue/cell, it sheds light on the current medical challenges including type-1 diabetes. Hence, biological repair mechanism including immune interaction needs to be understood in a clinically applicable fashion. The scarring remains in the immune cell, which is “mobile tools”, when prolonged burden against immune cell is experienced(13-15) including macrophage(16). On the other hand, neuroendocrine regulation including the cervical sympathetic trunk-submandibular gland (CST-SMG) axis may be associated with tissue repair(19). Therefore, systemic/systematic consideration about repair mechanism may be needed. Clinically, there is the viewpoint how we can enhance recovery of tissue/cell while taking advantage of “innate” recovery mechanism, meaning supplementary medicine.
 
(Reference)
(1)
Colin M. Dayan, Rachel E. J. Besser, Richard A. Oram, William Hagopian, Manu Vatish, Owen Bendor-Samuel, Matthew D. Snape, John A. Todd
Preventing type 1 diabetes in childhood
Science  30 Jul 2021: Vol. 373, Issue 6554, pp. 506-510
---
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Cardiff University School of Medicine, Cardiff, UK.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
Pacific Northwest Research Institute, Seattle, WA, USA.
Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK.
Department of Paediatrics, University of Oxford, Oxford, UK.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and Oxford NIHR Biomedical Research Centre, Oxford, UK.
(2)
L. M. Jacobsen, M. J. Haller, D. A. Schatz,
Front. Endocrinol. 9,70 (2018).
(3)
F. Pociot, Å. Lernmark,
Lancet 387, 2331 – 2339 (2016)
(4)
R. A. Insel et al.,
Diabetes Care 38, 1964 – 1974 (2015).
(5)
C. Kuhn, H. L. Weiner,
Immunotherapy 8, 889 – 906 (2016).
(6)
Jeffrey A. Bluestone, Jane H. Buckner, Kevan C. Herold
Immunotherapy: Building a bridge to a cure for type 1 diabetes
Science  30 Jul 2021: Vol. 373, Issue 6554, pp. 510-516
---
UCSF Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
Center for Translational Immunology, Benaroya Research Institute (BRI) at Virginia Mason, Seattle, WA, USA.
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101, USA.
Department of Immunobiology and Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
(7)
Nathaniel J. Hogrebe, Kristina G. Maxwell, Punn Augsornworawat & Jeffrey R. Millman
Generation of insulin-producing pancreatic β cells from multiple human stem cell lines
Nature Protocols (2021)
---
Affiliations
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
Nathaniel J. Hogrebe, Kristina G. Maxwell, Punn Augsornworawat & Jeffrey R. Millman
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
Kristina G. Maxwell, Punn Augsornworawat & Jeffrey R. Millman
(8)
Yu-Chen Chang et al.
Therapeutic Effects of BCG Vaccination on Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
J Diabetes Res. 2020; 2020: 8954125.
(9)
V. M. Stone et al.
A hexavalent Coxsackievirus B vaccine is highly immunogenic and has a strong protective capacity in mice and nonhuman primates
Science Advances  06 May 2020: Vol. 6, no. 19, eaaz2433
(10)
Décio L Eizirik, Stellan Sandler and Jerry P Palmer
Repair of Pancreatic β-cells: A Relevant Phenomenon in Early IDDM?
Diabetes 1993 Oct; 42(10): 1383-1391.
(11)
Dominika Nackiewicz et al.
Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1
iScience Volume 23, Issue 1, 24 January 2020, 100775
(12)
Todd M. Brusko, Holger A. Russ, Cherie L. Stabler
Strategies for durable b cell replacement in type 1 diabetes
Science  30 Jul 2021: Vol. 373, Issue 6554, pp. 516-522
---
Department of Pathology, Immunology and Laboratory Medicine, and Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
University of Florida Diabetes Institute, University of Florida, Gainesville, FL 32610, USA.
Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL 32610, USA.
(13)
Kathleen B. Yates, Pierre Tonnerre, Genevieve E. Martin, Ulrike Gerdemann, Rose Al Abosy, Dawn E. Comstock, Sarah A. Weiss, David Wolski, Damien C. Tully, Raymond T. Chung, Todd M. Allen, Arthur Y. Kim, Sarah Fidler, Julie Fox, John Frater, Georg M. Lauer, W. Nicholas Haining & Debattama R. Sen
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
Nature Immunology volume 22, pages1020–1029 (2021)
(14)
Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Aljabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, Damien C. Tully, Debattama R. Sen, David J. Bean, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, Ang Cui, David Lieb, James A. Cheney, Jenna Gustafson, Lia L. Lewis-Ximenez, Lucile Massenet-Regad, Thomas Eisenhaure, Jasneet Aneja, W. Nicholas Haining, Raymond T. Chung, Nir Hacohen, Todd M. Allen, Arthur Y. Kim & Georg M. Lauer
Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Nature Immunology volume 22, pages1030–1041 (2021)
(15)
Mohamed S. Abdel-Hakeem, Sasikanth Manne, Jean-Christophe Beltra, Erietta Stelekati, Zeyu Chen, Kito Nzingha, Mohammed-Alkhatim Ali, John L. Johnson, Josephine R. Giles, Divij Mathew, Allison R. Greenplate, Golnaz Vahedi & E. John Wherry
Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation
Nature Immunology volume 22, pages1008–1019 (2021)
(16)
Jonathan J Pinney et al.
Macrophage hypophagia as a mechanism of innate immune exhaustion in mAb-induced cell clearance
Blood. 2020 Oct 29;136(18):2065-2079.
(17)
Brennan, D. C., Kopetskie, H. A. & Sayre, P. H.
Long-term follow-up of the Edmonton protocol of islettransplantation in the United States.
Am. J. Transpl. 16, 509–517 (2016).
(18)
Shapiro, J. et al.
Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.
N. Engl. J. Med. 343, 230–238 (2000).
(19)
R Mathison et al.
Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors
Immunol Today. 1994 Nov;15(11):527-32.