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▎WuXi AppTec Content Team Editor Type 1 diabetes mellitus (T1D) is an organ-specific autoimmune disease that results from autoreactive T cells targeting β cells used to produce insulin in pancreatic islets as targets, resulting in severe impairment
of endogenous insulin secretion 。 Regulatory T cells (Tregs) are an important component of the human immune system and are important
for maintaining peripheral immune tolerance and preventing excessive immune responses and autoimmunity.
In recent years, with the deepening of research, Treg cells have been found to be closely related
to T1D.
Studies have shown that FOXP3+ Treg cells play a key role in maintaining islet-specific immune tolerance, and a decrease in the number or impaired function of Treg may be at the core of the pathogenesis of T1D, so increasing the number or functional activity of Treg cells has become a major candidate strategy
for the treatment and prevention of T1D.
However, the proportion of antigen-specific Treg cells in their natural state is extremely low, and existing in vitro expansion methods may disrupt the homeostatic equilibrium of Treg and transform it into effector T cells
。 Recently, the collaborative team of Benaroya Institute and Seattle Children's Institute in the United States successfully designed a highly efficient gene editing tool by combining the homology directed repair mechanism and lentiviral T cell receptor (TCR) delivery technology, generating long-lasting antigen-specific Tregs (EngTregs) cells from human primary CD4+ T cells, which monitor and inhibit the immune system when it begins to attack its own tissues, successfully preventing the occurrence of diabetes in mice.
The research results have been published in
Science-Translational Medicine, a sub-journal of the journal Science.
It is understood that this work builds on the research team's nearly ten years of work, after they have developed a class of Treg expressing the FOXP3 gene, the expression of which is one of the characteristics of Treg cells, and mutations or defects in this gene are associated
with Treg cell death 。 In previous studies, they designed Treg cells to successfully suppress effector T cells, and in this study, the scientists further made these cells more specific for islets β cells, thereby avoiding possible immunosuppression problems and improving their efficacy
.
In addition, the persistence of antigen-specific Treg cells in pancreatic tissue is critical
to producing long-term therapeutic outcomes.
Long-term observations in mouse models have shown that these Treg cells have successfully maintained a long-lasting therapeutic effect
.
At the end of the observation period, the scientists were pleasantly surprised to find that the EngTregs cells they had produced were similar
in abundance to the natural Tregs of the healthy control mice.
The findings of this study strongly support the great potential of EngTregs cells for the treatment of type 1 diabetes, which is expected to be used
in other organ-specific autoimmune diseases or inflammatory diseases.
Dr.
David Rawlings, one of the corresponding authors of the paper, is optimistic about the clinical translation prospects of this work, and he believes that this T-cell therapy will enter human clinical trials in the near future
.
Based on the paper's findings, Dr.
Rawlings and his team optimized their method for producing and expanding the EngTregs cell population for use in clinical trials, with preliminary results to be presented
at a recent international conference of the American Society for Cell and Gene Therapy (ASCGT).
of endogenous insulin secretion 。 Regulatory T cells (Tregs) are an important component of the human immune system and are important
for maintaining peripheral immune tolerance and preventing excessive immune responses and autoimmunity.
In recent years, with the deepening of research, Treg cells have been found to be closely related
to T1D.
Studies have shown that FOXP3+ Treg cells play a key role in maintaining islet-specific immune tolerance, and a decrease in the number or impaired function of Treg may be at the core of the pathogenesis of T1D, so increasing the number or functional activity of Treg cells has become a major candidate strategy
for the treatment and prevention of T1D.
However, the proportion of antigen-specific Treg cells in their natural state is extremely low, and existing in vitro expansion methods may disrupt the homeostatic equilibrium of Treg and transform it into effector T cells
。 Recently, the collaborative team of Benaroya Institute and Seattle Children's Institute in the United States successfully designed a highly efficient gene editing tool by combining the homology directed repair mechanism and lentiviral T cell receptor (TCR) delivery technology, generating long-lasting antigen-specific Tregs (EngTregs) cells from human primary CD4+ T cells, which monitor and inhibit the immune system when it begins to attack its own tissues, successfully preventing the occurrence of diabetes in mice.
The research results have been published in
Science-Translational Medicine, a sub-journal of the journal Science.
It is understood that this work builds on the research team's nearly ten years of work, after they have developed a class of Treg expressing the FOXP3 gene, the expression of which is one of the characteristics of Treg cells, and mutations or defects in this gene are associated
with Treg cell death 。 In previous studies, they designed Treg cells to successfully suppress effector T cells, and in this study, the scientists further made these cells more specific for islets β cells, thereby avoiding possible immunosuppression problems and improving their efficacy
.
The researchers combined two methods to construct Treg cells that are specific for antigens on islets β cells: they used a homology-directed repair mechanism to boost FOXP3 gene expression in Treg cells and human T cell receptor gene transfer
based on lentiviral vectors.
For the latter, they used seven different islet-specific T cell receptors, all derived from effector T cells isolated from patients with type 1 diabetes, to increase the specificity
of Treg cells for β islet cells in type 1 diabetes.
These antigen-specific Treg cells were experimentally tested to inhibit effector T cells in vitro, after which the researchers began testing the cells for in vivo activity
in mouse models.
They mixed these Treg cells with effector T cells and injected them into mice, which developed type 1 diabetes after injecting effector T cells, and observed their blood sugar levels
for the next 49 days.
Mice injected with antigen-specific Treg cells were almost completely free of diabetes at the end of observation, while those injected with a placebo developed diabetic symptoms between days 9 and 15
.
Image source: 123RF
In addition, the persistence of antigen-specific Treg cells in pancreatic tissue is critical
to producing long-term therapeutic outcomes.
Long-term observations in mouse models have shown that these Treg cells have successfully maintained a long-lasting therapeutic effect
.
At the end of the observation period, the scientists were pleasantly surprised to find that the EngTregs cells they had produced were similar
in abundance to the natural Tregs of the healthy control mice.
The findings of this study strongly support the great potential of EngTregs cells for the treatment of type 1 diabetes, which is expected to be used
in other organ-specific autoimmune diseases or inflammatory diseases.
Dr.
David Rawlings, one of the corresponding authors of the paper, is optimistic about the clinical translation prospects of this work, and he believes that this T-cell therapy will enter human clinical trials in the near future
.
Based on the paper's findings, Dr.
Rawlings and his team optimized their method for producing and expanding the EngTregs cell population for use in clinical trials, with preliminary results to be presented
at a recent international conference of the American Society for Cell and Gene Therapy (ASCGT).
As WuXi AppTec's CTDMO focused on cell and gene therapies, WuXi Biologics is committed to accelerating and transforming the development, testing, manufacturing and commercialization
of gene and cell therapies and other high-end therapies.
WuXi Biologics can help customers around the world bring more innovative therapies to market sooner rather than later, benefiting patients
.
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