Molecular mechanistic insights into how Teplizumab delays the development of autoimmune diabetes  (TIDM):  Teplizumab (also known as PRV-031/MGA031/hOKT3γ1), a humanized anti-CD3 monoclonal antibody,  increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and delays development of  type I diabetes (TIDM), via up-regulation of its target gene, 1/November/2019, 12.20 pm

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Introduction: What they say

A study from the International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, “L. Sacco” Department of Biomedical and Clinical Sciences, University of Milan, Milan 20157, Italy; and Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA shows that “PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.” This research paper was published, in the 15 November 2017 issue of the journal “Science Translational Medicine” [One of the best research journals in Science with an I.F of 15 plus], by Prof. Fiorina P and Nasr MB and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Molecular mechanistic insights into how Teplizumab delays the development of autoimmune diabetes  (TIDM):  Teplizumab (also known as PRV-031/MGA031/hOKT3γ1), a humanized anti-CD3 monoclonal antibody,  increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and delays development of  type I diabetes (TIDM), via up-regulation of its target gene, 1/November/2019, 12.20 pm


From significance of the study to public health relevance:

Given that: (1) more than 422 million people worldwide are affected by Diabetes mellitus (DM); (2) Type 1 Diabetes (T1DM) constitutes about 5-10% (11 to 12 million) of all diabetic cases; (3) the incidence of T1DM is exponentially increasing year after year by 3%; (4) Diabetes is going to be one of the top 10 causes of death by 2030; (5) the life-long painful injection/drug treatment is required to treat DM; (6) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, while treatment for T1DM costs about $15 billion dollars per annum, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM;(ii) a side-effect-free natural product-based drug that does not harm or deplete adult stem cells; and (iii) a way to cure, not just treat, diabetes.


What is known?

Prof. Fiorina’s research team has recently shown that:(1) programmed death ligand 1 (PD-L1), the immune checkpoint regulator, is expressed poorly in hematopoietic stem and progenitor cells (HSPCs) of Type-1 diabetic (T1D) patients; (2) PD-L1 inhibits activated T-cells and thereby promotes immune tolerance; (3) the expression of PD-L1 is controlled by a network of miRNAs; (4) attenuating the expression of one of the miRNAs that target PD-L1 restores the expression of PD-L1 in HSPCs; (5) increasing the expression of PD-L1 in HSPCs, either genetically or pharmacologically, inhibits autoimmune response and reverses autoimmune diabetes; and (6) PD-L1 is expressed poorly in human HSPCs of T1D patients, suggesting that increasing the expression of PD-L1 in T1D patients may reverse and cure T1D.


From research findings to Therapeutic opportunity:

A number of studies suggest that Teplizumab (also known as PRV-031/MGA031/hOKT3γ1(Ala-Ala), developed by Provention Bio, attenuates hyperglycemia, and may aid in the treatment of type I Diabetes.

A recent study from the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; the Departments of Epidemiology and Pediatrics, University of South Florida, Tampa, the Department of Medicine, University of Miami, Miami, and the Department of Pediatrics, University of Florida, Gainesville – all in Florida; Benaroya Research Institute, Seattle; the Diabetes Center, University of California at San Francisco, San Francisco; the Department of Pediatrics, Indiana University, Indianapolis; the Barbara Davis Diabetes Center, University of Colorado, Anschultz; Children’s Mercy Hospital, Kansas City, MO; the Department of Pediatrics, University of Minnesota, Minneapolis; the Department of Pediatrics and Cell and Developmental Biology, Vanderbilt University, Nashville; the Department of Pediatrics, University of Iowa, Iowa City; the Hospital for Sick Children, University of Toronto, Toronto; and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany shows the effect of “An Anti-CD3 , Teplizumab, in Relatives at Risk for Type 1 Diabetes.” This study was published, in the 9 June 2019 issue of of the prestigious journal N Engl J Med (Impact factor: 70+)by Prof. Herold KC, M.D., and others. This study suggests that treating relatives of type I diabetes patients, who were at high risk of developing clinical disease, with Teplizumab: (1)   resulted in median time to the diagnosis of type 1 diabetes was 48.4 months, in theTeplizumab group, while in placebo group, 24.4 months; and (2) delayed the development of type I diabetes, in the  relatives of type I diabetes patients.  However, the precise mechanism of action of Teplizumab remains largely unclear.

The study presented here substantiates and supports the aforementioned study’s’ claim, and of others, by providing detailed mechanistic insights into how Teplizumab delays or attenuates development of autoimmune diabetes. 

This study suggests, for the first time, with detailed mechanistic insights, that a pharmaceutical mixture encompassing Teplizumab can delay  autoimmune diabetes (TIDM-Type I diabetes). Teplizumab, by increasing the expression of its target gene, it may increase the expression of PD-L1, while decreasing the expression of TXNIP. Thereby, it may: (1) increase Regulatory T-cells(Tregs) function; and hematopoietic stem and progenitor cells (HSPCs); (2) decrease immune activation; (3) increase pancreatic-β-cell proliferation and regeneration; (4) increase the expression of genes that promote insulin sensitivity and insulin secretion;(4) decrease metabolic stress; and (5) promote glucose homeostasis (Fig.1).

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Teplizumab  inhibits the development of autoimmune diabetes (T1DM).  Teplizumab, by increasing the expression of its target genes, it may increase the expression of PD-L1, insulin, and other anti-diabetic genes, while decreasing the expression of TXNIP.  Thereby, it may prevent immune activation and attenuate the development of T1DM.

Figure 2. A pharmaceutical mixture encompassing Teplizumab functions as an anti-hyperglycemic agent (in autoimmune diabetes), by up regulating the expression of PD-L1 and other anti-diabetic genes, and by down regulating the expression of TXNIP.

Figure 3. While it had been that pharmacological activation of PD-L1 attenuates autoimmune diabetes, this study suggests for the first time that a pharmaceutical mixture encompassing Teplizumab promotes beta-cell regeneration and proliferation and delays development of autoimmune diabetes, through up regulation of PD-L1, and down regulation of TXNIP.

Figure 4. While it had been shown that Teplizumab delays the development of autoimmune diabetes, its mechanism of action remains unclear. This study suggests for the first time that a pharmaceutical mixture encompassing Teplizumab  promotes beta-cell regeneration and proliferation and delays or prevents autoimmune diabetes in relatives of patients with type I diabetes, through up regulation of PD-L1 and down regulation of TXNIP.

Thus, pharmacological formulations encompassing “Teplizumab or its functional or mechanistic equivalents, either alone or in combination with other drugs,” may be used to treat TIDM (Figs.2-4).

Given: (a) the mechanistic basis, and it matches perfectly with established scientific facts (figure 1), as to how Teplizumab may aid in delaying the development of type I diabetes in high-risk patients, medical practitioners/diabetologists may consider taking up this promising finding for further study.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Undisclosed information: How does Teplizumab increase the expression of PD-L1?

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Amount: $1, 500#

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References:

Web: http://genomediscovery.org or http://newbioideas.com

Citation: Boominathan, L.,  Molecular mechanistic insights into how Teplizumab delays the development of autoimmune diabetes  (TIDM):  Teplizumab (also known as PRV-031/MGA031/hOKT3γ1), a humanized anti-CD3 monoclonal antibody,  increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and delays development of  type I diabetes (TIDM), via up-regulation of its target gene, 1/November/2019, 12.20 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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