Exploration of Immune Targets for Type 1 Diabetes and Latent Autoimmune Disease Immunotherapy

Figures & data

Table 1 Islet Autoantibodies to Pancreatic Insulin-Producing Cells Secreted in T1D

Autoantigen	Expression	Subcellular Location	Function	References
Carboxypeptidase H/E	Neuroendocrine cells	Secretory granules	Proinsulin to insulin processing	[16]
Chromogranin A	Neuroendocrine cells	Secretory granules	Precursor of several biologically active peptides	[14,17]
Glutamic acid decarboxylase 65	Neuroendocrine cells	Synaptic like microvesicles	Gamma-aminobutyric Acid Synthesis	[18]
Glutamic acid decarboxylase 67	Islet cells, neurons	Synaptic like microvesicles	Gamma-aminobutyric Acid Synthesis	[19]
Glucose-regulated protein 78	Not restricted	Endoplasmic reticulum	Protein folding	[19]
Heat shock protein 60	Ubiquitous	Mitochondria	Protein folding	[20]
Insulinoma-associated antigen 2	Neuroendocrine cells	Secretory granules	Regulation of hormone secretion	[20]
Insulinoma- associated antigen-2β	Neuroendocrine cells	Secretory granules	Regulation of hormone secretion	[20]
Islets amyloid polypeptide (ppIAPP)	Beta cells	Secretory granules	Glucose homeostasis	[21]
Islet- cell antigen 69	Beta cells	Secretory granules	Unascertained	[22]
Islet-specific glucose-6 phosphatase catalytic subunit-related protein	Beta cells	Endoplasmic reticulum	Glucose metabolism	[23]
Insulin gene enhancer protein isl-1	Not restricted	Nucleus	DNA binding transcriptional factor	[24]
Pancreatic duodenal homeobox protein 1	Beta cells	Nucleus	Role in pancreas development, beta cell differentiation, and function	[25]
Peripherin	Neuroendocrine cells	Filaments	Unascertained	[26]
Pre-proinsulin, pro-insulin, insulin, oxidative post-translational modifications-insulin	Beta cells	Secretory granules	Glucose homeostasis	[25,27,28]
Prolyl 4 hydroxylase subunit β	Not restricted	Endoplasmic reticulum	Formation and rearrangement of disulfide bonds	[29]
Tetraspanin-7, Glima 38	Neuroendocrine cells	Plasma membrane	Signal transduction	[30]
Urocortin-3	Beta cells, alpha cells	Secretory granules	May regulate insulin secretion	[31]
Zinc transporter 8	Beta cells	Secretory granules	Zinc uptake in beta cell secretory granules	[32]

Note: Adapted with permission from Rodriguez-Fernandez S, Almenara-Fuentes L, Perna-Barrull D, Barneda B, Vives-Pi M. A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes. Immunol. Cell Biol. 2021;99: 461-474. © 2021 Australian and New Zealand Society for Immunology, Inc.³³

Table 2 Immune Interventions in T1D

Intervention	Immune Target	Immunotherapy Clinical Trial Study	References
AntiCD3 Mab (Teplizumab)	CD3	NCT01030861	[72]
CTLA4-Ig (Abatacept)	CD28/CD80/CD86	NCT01773707	[73]
Anakinra	IL-1 receptor	NCT00645840	[74]
Canakinumab	IL-1β	NCT00947427	[75]
Etanercept	TNF-α receptor	NCT00730392	[76]
Alum-formulated glutamate decarboxylase (GAD-Alum)	Glutamic acid decarboxylase antigen	NCT01785108	[77]
Imatinib Mesylate	Tyrosine kinase inhibitor	NCT01781975	[78]
Rituximab	CD20	NCT00279305	[79]
Teplizumab	CD3	NCT00385697	[80]
Anti-Thymocyte Globulin (ATG)/ Pegylated Granulocyte Colony Stimulating Factor (GCSF)	Thymoglobulin	NCT02215200	[81]
Mycophenolate Mofetil-Daclizumab	Inhibitor of inosine monophosphate dehydrogenase/ CD25	NCT00100178	[82]
Tocilizumab	IL-6R	NCT02293837	[83]
Bacillus Calmette-Guérin	TNF receptor 2	NCT02081326	[84]
Polyclonal regulatory T cells plus IL-2	Regulatory T cells and IL-2	NCT02772679	[85]
Tolerogenic Dendritic Cell Vaccine PIpepTolDCs	Autologous Tolerogenic Dendritic Cell with Proinsulin Peptide (PIpepTolDC)	NCT04590872	[86]
Simponi (Golimumab)	TNF-α	NCT03298542	[87]
Amevive (alefacept)	CD2	NCT00965458	[88]
Anti-interleukin-21 antibody and liraglutide	IL-21	NCT02443155	[89]

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