Posts Tagged ‘these’

Understanding, improving body’s fight against pathogens

While they exist in small populations in humans, the large amounts of antibodies secreted by plasma cells make them key to the body’s immune system and its ability to defend itself against pathogens, such as bacteria and viruses. Proper maintenance of a pool of plasma cells is also critical for the establishment of lifelong immunity elicited by vaccination.

Dysregulation of plasma cell production and maintenance could lead to autoimmune diseases and multiple myeloma. Autoimmune diseases occur when the immune system does not distinguish between healthy tissue and antigens, which are found in pathogens. This results in expansion of plasma cells which produce excessive amounts of antibodies leading to destruction of one’s own healthy tissue. The discoveries by scientists in BTI’s Immunology Group have improved understanding of the mechanism by which plasma cells are developed from a major class of white blood cells called B cells.

For the first time, the molecule DOK3 was found to play an important role in formation of plasma cells. While calcium signalling typically controls a wide range of cellular processes that allow cells to adapt to changing environments, it was found to inhibit the expression of the membrane proteins essential for plasma cell formation. These membrane proteins include PDL1 and PDL2, and represent some of the key targets for the development of immunotherapy by pharmaceutical companies. DOK3 was able to promote the production of plasma cells by reducing the effects of calcium signalling on these membrane proteins. The absence of DOK3 would thus result in defective plasma cell formation.

In another study, BTI scientists discovered the importance of SHP1 signalling to the long term survival of plasma cells. While the molecule SHP1 has a proven role in prevention of autoimmune diseases, it was found that the absence of SHP1 would result in the failure of plasma cells to migrate from the spleen where they are generated to the bone marrow, a survival niche where they are able to survive for much longer periods. This could result in a reduction of the body’s immune response and thus, an increased susceptibility to infections and diseases. The scientists in this study also successfully rectified the defective immune response caused by an absence of SHP1 by applying antibody injections, which might advance the development of therapeutics. On the other hand, targeting SHP1 might be a strategy to treat multiple myeloma where the accumulation of cancerous plasma cells in the bone marrow survival niches is undesirable.

Findings hold potential for improved treatment

The discovery of these new targets for modulating the antibody response allows the development of novel therapeutic strategies for patients with autoimmune diseases and cancer.Understanding the mechanism that governs plasma cell differentiation is also critical for the optimal design of vaccines and adjuvants, which are added to vaccines to boost the body’s immune response.

Prof Lam Kong Peng, Executive Director of BTI, said, “These findings allow better understanding of plasma cells and their role in the immune system. The identification of these targets not only paves the way for development of therapeutics for those with autoimmune diseases and multiple myeloma, but also impacts the development of immunological agents for combating infections.”

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Introducing the multi-tasking nanoparticle

“These are amazingly useful particles,” noted co-first author Yuanpei Li, a research faculty member in the Lam laboratory. “As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors; apply light to make the nanoparticles release singlet oxygen (photodynamic therapy) or use a laser to heat them (photothermal therapy) — all proven ways to destroy tumors.”

Jessica Tucker, program director of Drug and Gene Delivery and Devices at the National Institute of Biomedical Imaging and Bioengineering, which is part of the National Institutes of Health, said the approach outlined in the study has the ability to combine both imaging and therapeutic applications in a single platform, which has been difficult to achieve, especially in an organic, and therefore biocompatible, vehicle.

“This is especially valuable in cancer treatment, where targeted treatment to tumor cells, and the reduction of lethal effects in normal cells, is so critical,” she added.

Though not the first nanoparticles, these may be the most versatile. Other particles are good at some tasks but not others. Non-organic particles, such as quantum dots or gold-based materials, work well as diagnostic tools but have safety issues. Organic probes are biocompatible and can deliver drugs but lack imaging or phototherapy applications.

Built on a porphyrin/cholic acid polymer, the nanoparticles are simple to make and perform well in the body. Porphyrins are common organic compounds. Cholic acid is produced by the liver. The basic nanoparticles are 21 nanometers wide (a nanometer is one-billionth of a meter).

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers. At 32 nanometers, CNPs are ideally sized to penetrate tumors, accumulating among cancer cells while sparing healthy tissue.

In the study, the team tested the nanoparticles, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, CNPs effectively transported anti-cancer drugs, such as doxorubicin. Even when kept in blood for many hours, CNPs only released small amounts of the drug; however, when exposed to light or agents such as glutathione, they readily released their payloads. The ability to precisely control chemotherapy release inside tumors could greatly reduce toxicity. CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

CNPs also can be configured to respond to light, producing singlet oxygen, reactive molecules that destroy tumor cells. They can also generate heat when hit with laser light. Significantly, CNPs can perform either task when exposed to a single wavelength of light.

CNPs offer a number of advantages to enhance imaging. They readily chelate imaging agents and can remain in the body for long periods. In animal studies, CNPs congregated in tumors, making them easier to read on an MRI. Because CNPs accumulated in tumors, and not so much in normal tissue, they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans.

This versatility provides multiple options for clinicians, as they mix and match applications.

“These particles can combine imaging and therapeutics,” said Li. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

“These particles can also be used as optical probes for image-guided surgery,” said Lam. “In addition, they can be used as highly potent photosensitizing agents for intraoperative phototherapy.”

While early results are promising, there is still a long way to go before CNPs can enter the clinic. The Lam lab and its collaborators will pursue preclinical studies and, if all goes well, proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” said Li. “From delivering chemo, photodynamic and photothermal therapies to enhancing diagnostic imaging, it’s the complete package.”

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Natural killer cells battle pediatric leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. This disease hinders the development of healthy blood cells while cancer cells proliferate. Currently, children with ALL receive chemotherapy for two to three years, exposing them to significant side effects including changes in normal development and future fertility.

As a way to avoid these adverse effects, investigators have been researching how to supercharge the body’s innate cancer-fighting ability — a technique called immunotherapy. One branch of the immune system — and a possible component of immunotherapy — includes a class of cells called natural killer (NK) cells. These specialized white blood cells police the body and destroy abnormal cells before they turn cancerous.

Using NK cells as immunotherapy presents challenges. If the cells come from a donor, the patient might reject the cells or worse, be at risk for graft-versus-host disease — where contaminating donor cells regard the patient’s body as foreign and attack it. To avoid these problems, the researchers wondered if they could enlist the help of the patients’ own, or autologous, NK cells. Using autologous cells would remove the risks associated with donor cells.

But using autologous cells raised other issues. Would it be possible to multiply NK cells from patients with leukemia, even though they had very few to start with? Also, could the patient’s own NK cells attack their leukemia… and win?

“In this study, we used NK cells and ALL cells from the same pediatric patients. We found that autologous natural killer cells will destroy the patient’s leukemia cells,” said Nora Heisterkamp, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles and one of the co-lead investigators.

To help the NK cells identify their target as leukemia cells, the researchers also added a monoclonal antibody. Antibodies are normally made by cells of the immune system to identify and neutralize foreign material. Researchers can design and produce antibodies, called monoclonal antibodies (mAb), that specifically target a certain protein like the ones found on cancer cells. In a previous paper, Heisterkamp showed that a mAb targeted to a specific receptor (BAFF-R) on the leukemia cells stimulated the NK cells to attack and kill the cancer. The BAFF-R mAb was also used in this study.

“These results are very promising — with potential as a part of first line therapy and also as a treatment for eliminating any remaining cancer cells, known as minimal residual disease, following standard chemotherapy,” said Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles and co-lead investigator on the study. “We anticipate additional pre-clinical testing and then, a clinical trial to evaluate the therapy in children with leukemia.”

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