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First Working Synthetic Immune Organ With Controllable Antibodies

First Working Synthetic Immune Organ With Controllable Antibodies
When exposed to a foreign agent, such as an immunogenic protein, B cells in lymphoid organs (such as the spleen) undergo germinal center (immune defense) reactions. The image on the left is an normal immunized mouse spleen with activated B cells (brown) that produce antibodies. At right, top: a scanning electron micrograph of synthetic porous synthetic immune organoids that enable rapid proliferation and activation of B cells into antibody-producing cells. At right, bottom: primary B cell viability and distribution is visible 24 hours following encapsulation of B cells from the mouse lymphoid organ into the synthetic organoids. (credit: Singh Lab)

Click here to read the original article published on Kurzweil.

Cornell University engineers have created a functional, synthetic immune organoid (a lab-grown ball of cells with some of the features of a normal organ) that produces antibodies. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research.

The first-of-its-kind immune organoid was created in the lab of Ankur Singh, assistant professor of mechanical and aerospace engineering, who applies engineering principles to the study and manipulation of the human immune system.

Simulating the body’s immune response

The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from a hydrogel (a soft, nanocomposite gelatin-like biomaterial), reinforced with silicate nanoparticles to keep the structure from melting at body temperature.

This biomaterial is also seeded with B cells. It mimics the body’s normal anatomical microenvironment of lymphoid tissue, which produces lymphocytes and antibodies in the lymph nodes, thymus, tonsils, and spleen.

Like a real organ, the organoid converts B cells — which make antibodies that respond to infectious invaders — into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. (Germinal centers are a sign of infection and are not present in healthy immune organs.)

The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D lab cultures and can produce activated B cells up to 100 times faster.

A new tool for studying immune functions

Silicate nanoparticles
Silicate nanoparticles (SiNP) are used for ionic crosslinking of gelatin to form stable hydrogel at body temperature (credit: Alberto Purwada et al./Biomaterials)

According to Singh, the organoid could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature, and could also be used to study specific infections and how the body produces antibodies to fight those infections — from Ebola to HIV.

“You can use our system to force the production of immunotherapeutics at much faster rates,” he said. Such a system also could be used to test toxic chemicals and environmental factors that contribute to infections or organ malfunctions.

The process of B cells becoming germinal centers is not well understood, and in fact, when the body makes mistakes in the genetic rearrangement related to this process, blood cancer can result.

“In the long run, we anticipate that the ability to drive immune reaction ex vivo [outside the body] at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs,” Singh said.

The work was published online June 3 in Biomaterials and will appear later in print.


Abstract of Ex vivo Engineered Immune Organoids for Controlled Germinal Center Reactions

Ex vivo engineered three-dimensional organotypic cultures have enabled the real-time study and control of biological functioning of mammalian tissues. Organs of broad interest where its architectural, cellular, and molecular complexity has prevented progress in ex vivo engineering are the secondary immune organs. Ex vivo immune organs can enable mechanistic understanding of the immune system and more importantly, accelerate the translation of immunotherapies as well as a deeper understanding of the mechanisms that lead to their malignant transformation into a variety of B and T cell malignancies. However, till date, no modular ex vivo immune organ has been developed with an ability to control the rate of immune reaction through tunable design parameter. Here we describe a B cell follicle organoid made of nanocomposite biomaterials, which recapitulates the anatomical microenvironment of a lymphoid tissue that provides the basis to induce an accelerated germinal center (GC) reaction by continuously providing extracellular matrix (ECM) and cell-cell signals to naïve B cells. Compared to existing co-cultures, immune organoids provide a control over primary B cell proliferation with ∼100-fold higher and rapid differentiation to the GC phenotype with robust antibody class switching.

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Type 1 Diabetes Baby

Type 1 Diabetes Originates in the Gut But Probiotics Could Offer Cure

Two separatType 1 Diabetes Babye pieces of research have found that the development of type 1 diabetes is likely caused by the gut, and therefore, a type of probiotic could be the cure.

Scientists from several European and US institutions studied 33 Finnish infants over three years from birth who were genetically predisposed to type 1 diabetes.

Their study, entitled “The Dynamics of the Human Infant Gut Microbiome in Development and in Progression toward Type 1 Diabetes” is published in the journal Cell Host & Microbe.

They discovered that four children in the group that developed type 1 diabetes had 25% less types of bacteria in their guts than other children.

The same four infants were also found to have more amounts of a specific bacteria that is known to trigger gut inflammation. This could be a prelude to type 1 diabetes as the bacteria causes the immune system to mistakenly attack and destroy beta cells in the pancreas that usually make insulin and monitor glucose levels.

“We know from previous human studies that changes in gut bacterial composition correlate with the early development of type 1 diabetes, and that the interactions between bacterial networks may be a contributing factor in why some people at risk for the disease develop type 1 diabetes and others don’t,” said Jessica Dunne, Director of Discovery Research at Juvenile Diabetes Research Foundation (JDRF), a UK charity which funded the study.

“This is the first study to show how specific changes in the microbiome are affecting the progression to symptomatic T1D.”

By being able to understand how the community of microorganisms in our guts (known as a microbiome) and which species are absent in the gastrointestinal tracts of children, the researchers believe they can slow down the progression of type 1 diabetes.

Probiotics could be the cure for type 1 diabetes

Cornell University researchers have a similar idea, but they have been working on a treatment that involves regulating insulin by engineering the bacteria found in our guts.

Their study, entitled “Engineered Commensal Bacteria Reprogram Intestinal Cells Into Glucose-Responsive Insulin-Secreting Cells for the Treatment of Diabetes” is published in the journal Diabetes.

The scientists took a strain of bacteria known as Lactobacillus gasseri – a type of bacteria found in probiotic yoghurts – and engineered the bacteria to be able to secrete a hormone called glucagon-like peptide-1 (GLP-1).

When they fed this engineered probiotic to a group of diabetic rats for 90 days, they discovered that the bacteria triggered the upper intestinal epithelial cells in the rats to convert into cells that acted a lot like the pancreatic beta cells.

The rats had up to 30% lower high blood glucose than diabetic rats that did not receive the probiotic, and the probiotic was shown to reduce glucose levels in diabetic rats the same way the levels would be reduced in normal rats.

“The amount of time to reduce glucose levels following a meal is the same as in a normal rat… and it is matched to the amount of glucose in the blood. It’s moving the centre of glucose control from the pancreas to the upper intestine,” said John March, professor of biological and environmental engineering at Cornell University and the paper’s senior author.

The next step for March and his team is to prove that their method of engineering bacteria to move insulin production to the intestine will work in humans too.

They aim to develop a pill that patients suffering from both type 1 and type 2 diabetes can take daily, that will be available within the next two years.

 

To learn how you can get more involved in the DRC’s research projects visit: Support a Diabetes Research Project

 

Source:

http://www.ibtimes.co.uk/type-1-diabetes-originates-gut-probiotics-could…

 

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