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

63 Pages Posted: 2 Feb 2021 Publication Status: Review Complete

See all articles by Shahnawaz Imam

Shahnawaz Imam

University of Toledo - Division of Endocrinology, Diabetes and Metabolism

Pervaiz Dar

University of Toledo - Division of Endocrinology, Diabetes and Metabolism

Maria Alfonso-Jaume

University of Toledo - Division of Nephrology and Transplant Nephrology

Ahmed Al-Khudhair

University of Toledo - Division of Endocrinology, Diabetes and Metabolism

Juan Carlos Jaume

University of Toledo - Division of Endocrinology, Diabetes and Metabolism

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Abstract

We have generated a new transgenic mouse model of Type 1 Diabetes (T1D) in which mouse Major Histocompatibility Complex-II (MHC-II) molecules were replaced with human DQ8 in all antigen-presenting cells. Our mice also express human Glutamic Acid Decarboxylase, isoform 65 (GAD65) in pancreatic beta cells as humans do. Our humanized mouse-model has the closest known phenotype to human T1D and is most suitable for addressing pathophysiology and treatment of the disease. To that end, we have developed pancreatic beta-cell, antigen-specific, Chimeric Antigen Receptor (CAR) T regulatory cells (Tregs) and explored their therapeutic potential against T1D.  Ours is the first report of a successful, antigen-specific CAR-Treg treatment of T1D in a new model that closely resembles the human disease. Conceivably, treatment with antigen-specific CAR-Tregs will allow for recovery and reconstitution of beta cells in humans as well.

Keywords: Type 1 Diabetes, Autoimmune Diabetes, Latent Autoimmune Diabetes of Adults, Humanized Transgenic Models, Regulatory T cells, Chimeric Antigen Receptor, Adoptive Cell Transfer

Suggested Citation

Imam, Shahnawaz and Dar, Pervaiz and Alfonso-Jaume, Maria and Al-Khudhair, Ahmed and Jaume, Juan Carlos, Spontaneous Type-1-Diabetes Humanized Transgenics Help Unveil Pathophysiology of Human Diabetes and Allow for Disease-Reverting CAR-Treg Immunotherapy. Available at SSRN: https://ssrn.com/abstract=3778362 or http://dx.doi.org/10.2139/ssrn.3778362
This version of the paper has not been formally peer reviewed.

Shahnawaz Imam

University of Toledo - Division of Endocrinology, Diabetes and Metabolism ( email )

Toledo, OH
United States

Pervaiz Dar

University of Toledo - Division of Endocrinology, Diabetes and Metabolism ( email )

Toledo, OH
United States

Maria Alfonso-Jaume

University of Toledo - Division of Nephrology and Transplant Nephrology ( email )

United States

Ahmed Al-Khudhair

University of Toledo - Division of Endocrinology, Diabetes and Metabolism ( email )

Toledo, OH
United States

Juan Carlos Jaume (Contact Author)

University of Toledo - Division of Endocrinology, Diabetes and Metabolism ( email )

Toledo, OH
United States

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