A step towards a Type 1 Diabetes vaccine by using nanotherapy

Two years ago, the Immunology of Diabetes Research Group at the Germans Trias i Pujol Research Institute, member of the UAB-CIE Sphere, reported a new experimental immunotherapy that prevented the onset of Type 1 Diabetes in mice predisposed to the disease. This work led to more studies with the support of the Spanish Government, Catalan Government and private patrons with a keen interest in it. Thanks to this, a new step towards the creation of a vaccine has been made, which in the medium-term could be capable of preventing and even curing the disease in humans. The article published today in the scientific journal PLOS ONE describes this new step towards the creation of a vaccine.

Initially the researchers avoided the destruction of the insulin-producing pancreatic cells (beta cells) in the body by modifying the individual’s immune cells, known as dendritic cells. This important step requires the extraction of the subjects' dendritic cells for their subsequent manipulation and re-injection. The process is complex and costly. In a new study with mice researchers have achieved the same effect with a much simpler process. Nanoparticles called liposomes are created in the laboratory; when they are introduced into the body they arrest the destruction of the beta cells and avoid Diabetes development. This technique could be a much better candidate for a human vaccine. The invention is commercially protected and an international patent has been applied for.

Droplets of fat and water which can be produced on a large scale

Liposomes have been used in several medical treatments. They are not cells, but droplets with an external fat membrane, similar to cell membranes. They can be made using a very specialized process, but one that is easy and safe and also easy to scale up.

The key: beta cells in process of natural death

To complete this study Germans Trias researchers have worked together with a ICREA group from the Catalan Institute for Nanoscience and Nanotechnology (ICN2). The ICN2 is a Severo Ochoa Centre of Research Excellence located on Universitat Autònoma de Barcelona (UAB) Campus, and its mission is to seek nanotechnology solutions to challenges in the fields of biology, energy or technology. The diameter of the liposomes created for this collaborative work is from half to one micron. They were specifically generated to imitate beta cells of the pancreas that are in the process of programmed cell death (apoptosis). As the researchers showed during the previous studies, this is the way to prevent the body from destroying the beta cells and to allow it to recuperate immunological tolerance. The Catalan researchers are the first group in the world to use liposomes that imitate naturally dying cells to fight against Diabetes. The Universities of Barcelona and Lleida also contributed to this work.

Next steps 

After showing that liposomes prevent the onset of Type 1 Diabetes in mice, the next steps are to test it in human cells in vitro, to start clinical trials on human candidates for preventive vaccination and to cure the disease by combining the vaccine with regenerative therapies. The Germans Trias Institute plans to carry out these steps with patients at the hospital and to optimise the product by dosage and guideline studies. It is also planned to optimise the product for personalization. To achieve these objectives more competitive funding will be necessary from public agencies. The group is also studying collaborations and investment opportunities from the pharmaceutical industry. Private funding continues to be important and the Germans Trias Institute is studying the possibility of organizing a local campaign.

Growing incidence and complex consequences 
Type 1 Diabetes is an illness where the body does not recognize the beta cells of the pancreas as its own and destroys them. The organ produces less and less insulin, the hormone that allows us to process the sugar we eat. Patients must prick their fingers several times a day to check blood sugar levels and inject themselves with insulin in the stomach or other parts of the body. This constant control is not always easy and having too much or too little insulin can have severe consequences. The most serious is that in the long term hyperglycaemia provokes retinal damage that can lead to blindness, renal insufficiency, destruction of nerve fibres or what is called "Diabetics Foot" where ulcers form, leading eventually to the need to amputate.

The causes of the disease are unknown, although there are both genetic and environmental factors involved. About 0.3% of the population is affected and the incidence is increasing by 3-4% a year. It usually appears in children and young adults and it is incurable. This immunotherapy presents a possible solution for Type 1 Diabetes.

Source: http://www.nanotechnologyworld.org/#!A-step-towards-a-Type-1-Diabetes-vaccine-by-using-nanotherapy/c89r/5577096b0cf293eac807083b 

Nanoparticles target anti-inflammatory drugs where needed

Bottom right shows green-labeled neutrophils with
red-labeled nanoparticles inside, which appear yellow

Researchers at the University of Illinois at Chicago have developed a system for precisely delivering anti-inflammatory drugs to immune cells gone out of control, while sparing their well-behaved counterparts. 

Their findings were published online Feb. 23 in Nature Nanotechnology. The system uses nanoparticles made of tiny bits of protein designed to bind to unique receptors found only on neutrophils, a type of immune cell engaged in detrimental acute and chronic inflammatory responses. 

In a normal immune response, neutrophils circulating in the blood respond to signals given off by injured or damaged blood vessels and begin to accumulate at the injury, where they engulf bacteria or debris from injured tissue that might cause infection. In chronic inflammation, neutrophils can pile up at the site of injury, sticking to the blood vessel walls and to each other and contributing to tissue damage. 

Adhesion of neutrophils to blood vessel walls is a major factor in acute lung injury, where it can impair the exchange of gases between the lungs and blood, leading to severe breathing problems. If untreated, the disease has a 50 percent mortality rate in intensive care units.

Corticosteroids and non-steroidal anti-inflammatory drugs used to treat inflammatory diseases are “blunt instruments that affect the whole body and carry some significant side effects,” says Asrar B. Malik, the Schweppe Family Distinguished Professor and head of pharmacology in the UIC College of Medicine, who is lead author of the paper. 

Neutrophils that are stuck to blood vessels or clumped together have unique receptors on their surface that circulating neutrophils lack. Malik and his colleagues designed a nanoparticle to take advantage by embedding it with an anti-inflammatory drug. 

The nanoparticles bind to the receptors, and the neutrophils internalize the nanoparticle. Once inside, the anti-inflammatory drug works to “unzip” the neutrophil and allow it to re-enter the bloodstream. “The nanoparticle is very much like a Trojan horse,” Malik said. “It binds to a receptor found only on these activated, sticky neutrophils, and the cell automatically engulfs whatever binds there. 

Because circulating neutrophils lack these receptors, the system is incredibly precise and targets only those immune cells that are actively contributing to inflammatory disease.” Malik, along with research assistant professor Zhenjia Wang and assistant professor Jaehyung Cho, used intra-vital microscopy to follow nanoparticles in real-time in mice with induced vascular inflammation. 

The nanoparticles were labeled with a fluorescent dye, and could be seen binding to and entering neutrophils clustered together on the inner walls of capillaries, but not binding to freely circulating neutrophils. If the researchers attached a drug called piceatannol, which interferes with cell-cell adhesion, to the nanoparticles, they observed that clusters of neutrophils that took up the particles detached from each other and from the blood vessel wall. 

The cells were in effect neutralized and could no longer contribute to inflammation at the site of an injury. The findings, Malik said, “show that nanoparticles can be used to deliver drugs in a highly targeted, specific fashion to activated immune cells and could be designed to treat a broad range of inflammatory diseases.” Jing Li, postdoctoral research associate in pharmacology, was also a co-author of the study. The research was supported by grants 11SDG7490013 from the American Heart Association, and grants K25HL11157, R01 HL109439 and P01 HL77806 from the National Institutes of Health

Source: http://news.uic.edu/nanoparticles-target-anti-inflammatory-drugs-where-needed#sthash.BLg29h7O.dpuf

On-demand vaccines possible with engineered nanoparticles

This image shows a collection of vaccinating nanoparticles, which at
their largest are about 1,000 times smaller than a human hair. The
inset graphic is a representation of how the engineered proteins
decorate a nanoparticle’s surface.
Credit: University of Washington

Vaccines combat diseases and protect populations from outbreaks, but the life-saving technology leaves room for improvement. Vaccines usually are made en masse in centralized locations far removed from where they will be used. They are expensive to ship and keep refrigerated and they tend to have short shelf lives.

University of Washington engineers hope a new type of vaccine they have shown to work in mice will one day make it cheaper and easy to manufacture on-demand vaccines for humans. Immunizations could be administered within minutes where and when a disease is breaking out.

“We’re really excited about this technology because it makes it possible to produce a vaccine on the spot. For instance, a field doctor could see the beginnings of an epidemic, make vaccine doses right away, and blanket vaccinate the entire population in the affected area to prevent the spread of an epidemic,” said François Baneyx, a UW professor of chemical engineering and lead author of a recent paper published online in the journal Nanomedicine.

The research was funded by a Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation and the National Institutes of Health.

In typical vaccines, weakened pathogens or proteins found on the surface of microbes and viruses are injected into the body along with compounds called adjuvants to prepare a person’s immune system to fight a particular disease. But standard formulations don’t always work, and the field is seeking ways to manufacture vaccines quicker, cheaper and tailored to specific infectious agents, Baneyx said.

The UW team injected mice with nanoparticles synthesized using an engineered protein that both mimics the effect of an infection and binds to calcium phosphate, the inorganic compound found in teeth and bones. After eight months, mice that contracted the disease made threefold the number of protective “killer” T-cells – a sign of a long-lasting immune response – compared with mice that had received the protein but no calcium phosphate nanoparticles.

The nanoparticles appear to work by ferrying the protein to the lymph nodes where they have a higher chance of meeting dendritic cells, a type of immune cell that is scarce in the skin and muscles, but plays a key role in activating strong immune responses.

In a real-life scenario, genetically engineered proteins based on those displayed at the surface of pathogens would be freeze-dried or dehydrated and mixed with water, calcium and phosphate to make the nanoparticles. This should work with many different diseases and be especially useful for viral infections that are hard to vaccinate against, Baneyx said.

He cautioned, however, that it has only been proven in mice, and the development of vaccines using this method hasn’t begun for humans.

The approach could be useful in the future for vaccinating people in developing countries, especially when lead time and resources are scarce, Baneyx said. It would cut costs by not having to rely on refrigeration, and vaccines could be produced with rudimentary equipment in more precise, targeted numbers. The vaccines could be manufactured and delivered using a disposable patch, like a bandage, which could one day lessen the use of trained personnel and hypodermic needles.

Co-authors of the paper are Weibin Zhou, Albanus Moguche and David Chiu of the UW, and Kaja Murali-Krishna of Emory University.

Source: http://www.washington.edu/news/2014/01/07/on-demand-vaccines-possible-with-engineered-nanoparticles/