Spontaneous Type-1-Diabetes Humanized Transgenics Help Unveil Pathophysiology of Human Diabetes and Allow for Disease-Reverting CAR-Treg Immunotherapy

2021 ◽  
Author(s):  
Shahnawaz Imam ◽  
Pervaiz Dar ◽  
Maria Alfonso-Jaume ◽  
Ahmed Al-Khudhair ◽  
Juan Carlos Jaume
Keyword(s):  
Type 1 Diabetes ◽  
Human Diabetes

scholarly journals P0681TIMP-1 DEFICIENCY DAMPENS RENAL GALECTIN-3 RESPONSE IN DIABETES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Gabor Kokeny ◽  
Helga Popovics ◽  
Krisztina Mikone ◽  
Miklos Mozes
Keyword(s):  
Type 1 Diabetes ◽  
Fasting Blood Glucose ◽  
Tubular Damage ◽  
Lipocalin 2 ◽  
Wild Type ◽  
Ccl2 Expression ◽  
Human Diabetes ◽  
Galectin 3 ◽  
Tissue Inhibitors Of Metalloproteases

Abstract Background and Aims Overexpression of tissue inhibitors of metalloproteases (TIMPs) are a hallmark of renal fibrosis, and elevated TIMP-1 has been reported in experimental and human diabetes. Also, renal galectin-3 (Lgals3) overproduction might link macrophages to fibrosis progression. However, the possible association of renal Lgals3 with TIMP-1 in diabetes is still unclear. Thus, we investigated nephropathy and renal Lgals3 in type-1 diabetic wild type and TIMP-1 knockout (KO) mice. Method Type-1 diabetes was induced in 6 week-old male TIMP-1 KO (DM KO, n=7) and wild type (DM, n=6) mice with daily intraperitoneal streptozotocin (50 mg/kg/day) injections for 5 consecutive days. Non-diabetic controls (CTL, n=5) were injected with vehicle. Fasting blood glucose was monitored, and after 8 weeks kidneys were analyzed for histology and mRNA expression. Results Both diabetic groups developed similar hyperglycemia (CTL: 6±2, DM: 29±5, DM KO: 33±7 mmol/l, p<0.01). However, serum creatinine was elevated only in wild type diabetic mice (CTL: 9±2, DM: 47±28, DM KO: 11±2 ug/dl, p<0.001). Histology revealed significant tubular damage in DM mice (score: CTL: 0.4±0.1, DM: 2.3±0.2, DM KO: 1.6±0.2, p<0.05), accompanied by 10-fold lipocalin-2 (CTL: 1.0±0.3, DM: 10.9±6.2, DM KO: 3.3±1.7, p<0.05) and 2-fold collagen-1 overexpression (CTL: 1.0±0.2, DM: 1.9±0.7, DM KO: 1.2±0.4, p<0.05), practically absent in diabetic KO kidneys. Similarly, TIMP-1 deficiency was associated with twofold decrease in renal Lgal3 (CTL: 1.0±0.6, DM: 2.0±1.1, DM KO: 0.8±0.3, p<0.05) and tenfold decrease in CCL2 expression levels (CTL: 1.0±0.3, DM: 20.2±4.2, DM KO: 2.3±1.5, p<0.01) as compared to DM. Conclusion In our model of type-1 diabetes, TIMP-1 deficiency attenuated the development of renal fibrotic and inflammatory response by reducing galectin-3 and CCL2 (MCP-1), preserved tubular integrity and renal function. This might implicate TIMP-1 to be a possible therapeutic target in the future.

scholarly journals The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes 2013;62:531-542

Diabetes ◽  
2013 ◽  
Vol 62 (7) ◽  
pp. 2623-2623
Author(s):  
E. Korpos ◽  
N. Kadri ◽  
R. Kappelhoff ◽  
J. Wegner ◽  
C. Overall ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Basement Membrane ◽  
Human Diabetes

scholarly journals A mutant α1antitrypsin in complex with heat shock proteins as the primary antigen in type 1 diabetes in silico investigation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paola Finotti ◽  
Andrea Pagetta
Keyword(s):  
Type 1 Diabetes ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
In Silico ◽  
Sequence Similarity ◽  
Hybrid Peptides ◽  
Human Diabetes ◽  
Shock Proteins ◽  
Specific Sequences

AbstractBased on previous results demonstrating that complexes of a mutant α1-antitrypsin with the heat shock proteins (HSP)70 and glucose-regulated protein94 (Grp94) circulate in the blood of patients with type 1 diabetes, we raised the hypothesis that these complexes could represent the primary antigen capable of triggering the autoimmune reactions leading to overt diabetes. As a first approach to this issue, we searched whether A1AT and HSPs had a sequence similarity to major islet antigen proteins so as to identify among the similar sequences those with potential relevance for the pathogenesis of diabetes. A thorough in silico analysis was performed to establish the score of similarity of the human proteins: A1AT, pro-insulin (INS), GAD65, IAPP, IA-2, ICA69, Grp94, HSP70 and HSP60. The sequences of A1AT and HSPs with the highest score of similarity to the islet peptides reported in the literature as the main autoantigens in human diabetes were recorded. At variance with other HSPs, also including HSP90 and Grp78, Grp94 contained the highest number and the longest sequences with structural similarity to A1AT and to well-known immunogenic peptides/epitopes of INS, GAD65, and IA-2. The similarity of A1AT with Grp94 and that of Grp94 with INS also suggested a functional relationship among the proteins. Specific sequences were identified in A1AT, Grp94 and HSP70, with the highest score of cross-similarity to a pattern of eight different islet protein epitopes. The similarity also involved recently discovered autoantigens in type 1 diabetes such as a hybrid peptides of insulin and the defective ribosomal insulin gene product. The significant similarity displayed by specific sequences of Grp94 and A1AT to the islet peptides considered main antigens in human diabetes, is a strong indication for testing these sequences as new peptides of immunogenic relevance in diabetes.

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