{"id":1933,"date":"2024-12-12T04:18:40","date_gmt":"2024-12-12T04:18:40","guid":{"rendered":"https:\/\/happy-liskov.74-208-176-141.plesk.page\/2024\/?p=1933"},"modified":"2025-01-28T03:34:02","modified_gmt":"2025-01-28T03:34:02","slug":"cami-scientists-determined-to-develop-new-treatments-for-autoimmune-diseases","status":"publish","type":"post","link":"https:\/\/annualreports.healthsciences.arizona.edu\/2024\/cami-scientists-determined-to-develop-new-treatments-for-autoimmune-diseases\/","title":{"rendered":"CAMI scientists determined to develop new treatments for autoimmune diseases"},"content":{"rendered":"

People have been waiting a long time for a cure for Type 1 diabetes.\u00a0<\/span>Hannah Pizzato, PhD<\/b>, is one of them.<\/span><\/p>\n

Pizzato was diagnosed with Type 1 diabetes when she was 4 years old. She was too young to understand it is an autoimmune disease. She didn\u2019t know her immune system was attacking cells in her pancreas that are responsible for producing insulin, a hormone that regulates blood sugar. But from an early age, she began to question why people become sick.<\/span><\/p>\n

\u201cMy whole life I was told a cure is coming and that I won\u2019t have to deal with this very long, but then a cure never came,\u201d said Pizzato, a principal scientist at the\u00a0<\/span>University of Arizona Health Sciences<\/b><\/a>\u00a0<\/span>Center for Advanced Molecular and Immunological Therapies<\/b><\/a>.\u00a0\u201cI was always interested in the fundamentals of how the body works and adapts over time to keep us alive,\u201d she said. \u201cI was intrigued by how biology influences human development.\u201d<\/span><\/p>\n

It isn\u2019t a surprise her educational and research trajectory focused on the immune system and Type 1 diabetes. As one of the first scientists working at CAMI, Pizzato is building upon research done under the mentorship of\u00a0<\/span>Deepta Bhattacharya, PhD<\/b>, the inaugural executive director of CAMI, with the goal of one day using a stem cell therapy to finally cure Type 1 diabetes.\u00a0<\/span><\/p>\n

\"\"
(From left) Deepta Bhattacharya, PhD, began mentoring Hannah Pizzato, PhD, when she started her doctoral studies at Washington University in St. Louis. She followed him to the University of Arizona Health Sciences and is one of the first principal scientists at the Center for Advanced Molecular and Immunological Therapies.<\/figcaption><\/figure>\n

Since the first successful bone marrow transplant in 1956, scientists all over the world have been examining stem cells and their potential to fight diseases, regenerate damaged tissues and develop personalized treatments for patients. Today, hematopoietic stem cells found in bone marrow are used to treat blood cancers such as leukemia, lymphoma, multiple myeloma and more.\u00a0<\/span><\/p>\n

One of the fastest-growing areas of stem cell research utilizes pluripotent stem cells, which are cells that can turn into any cell type in the body.\u00a0Pizzato\u2019s goal is to turn them into insulin-producing beta cells to replace the ones lost to Type 1 diabetes.\u00a0<\/span><\/p>\n

The biggest challenge comes from the immune system, which fights off infections, diseases and, unfortunately, regenerative treatments including stem cells.\u00a0Bhattacharya and Pizzato have spent years trying to find a solution to this problem. Now, they may be on the verge of a breakthrough.<\/span><\/p>\n

\"\"
Stem-cell research at CAMI could lead to stem cell-based therapies that can bypass the body\u2019s immune system and target diseases.<\/figcaption><\/figure>\n

Pizzato was the first author on a paper published in\u00a0<\/span>Stem Cell Reports<\/b><\/a>\u00a0that detailed how the research team genetically engineered stem cells to evade detection by the immune system.<\/span><\/p>\n

T cells, a type of white blood cell, are key drivers of immune rejection. They constantly scan for anything that doesn\u2019t belong in the body, such as viruses and bacteria, and perform security checks by looking for human leukocyte antigen, a protein found on the surface of most cells. If the protein isn\u2019t a match to the body\u2019s specific human leukocyte antigen, the T cell is triggered to kill that cell.\u00a0<\/span><\/p>\n

\u201cTo get around this problem, we used a genetic engineering tool to cut out the gene that encodes for that protein,\u201d Pizzato said. \u201cThis acts as a camouflage to get our modified stem cells around any investigating T cells.\u201d<\/span><\/p>\n

The lack of human leukocyte antigen solved the T cell problem, but it didn\u2019t address two other parts of the immune system: natural killer cells and complement deposition. Natural killer cells, like T cells, are always on the lookout to destroy damaged or diseased cells. The immune system also relies on a process called complement deposition, where certain proteins bind to the surface of invaders to help the immune system recognize threats.<\/span><\/p>\n

Pizzato said that after removing human leukocyte antigen, the team added several other proteins, some of which sent inhibitory signals to hinder the natural killer cells and others preventing complement deposition.<\/span><\/p>\n

\u201cIt\u2019s like we took the stem cell\u2019s glasses off, and then added a hat, fake moustache and coat to prevent recognition,\u201d Pizzato said.\u00a0<\/span><\/p>\n

The modified stem cells were tested in mice with fully functioning immune systems, where they successfully dodged rejection by the immune system and persisted.\u00a0<\/span><\/p>\n

\u201cThese findings are very encouraging and give us confidence we are ready to move forward,\u201d Pizzato said.\u00a0<\/span><\/p>\n

Advancing CAR T cell therapy with biomimetic design<\/b><\/p>\n

Humans have a long history of borrowing from nature to advance technology. It is a concept that researchers <\/span>Mark Lee<\/b>\u00a0and\u00a0<\/span>Michael Kuhns, PhD<\/b>, at the University of Arizona Health Sciences, employ to study the natural mechanisms behind how immune cells function to generate immunological therapies.\u00a0<\/span><\/p>\n

\"\"
(From left) Research scientist Mark Lee has worked for professor and immunologist Michael Kuhns, PhD, for years. Lee is now opening his own lab at CAMI in Phoenix.<\/figcaption><\/figure>\n

\u201cOur understanding of biology and the internal mechanisms that sustain life is ever increasing,\u201d Lee said. \u201cThe idea that we can mimic some of what we know about nature to create new technologies and treatments is amazing to me.\u201d\u00a0<\/span><\/p>\n

For more than a decade, Lee worked alongside Kuhns, a professor in the U of A\u00a0<\/span>College of Medicine \u2013 Tucson\u2019s Department of Immunobiology<\/b><\/a>, to improve CAR T cell therapy, an immunotherapy used to treat certain types of cancer.<\/span><\/p>\n

CAR T cells are manufactured by collecting a patient\u2019s T cells and engineering them to produce chimeric antigen receptors, or CARs, that are designed to bind to certain proteins on cancer cells. The CAR T cells are transfused back into the patient, where they can go to work killing cancer cells.<\/span><\/p>\n

\u201cCAR T cell therapy has been a breakthrough, but it can sometimes be ineffective and also runs the risk of a severe inflammatory response,\u201d said Kuhns, who is CAMI\u2019s senior scientific advisor. \u201cSince the fundamental design of CARs is based on an early-1990s understanding of T cell biology, we think there is room for improvement. We\u2019ve learned a lot more about these molecular machines since then.\u201d<\/span><\/p>\n

Today, scientists have a much more detailed understanding of what drives T cell activation. In nature, each T cell contains a receptor complex made up of five components: the antigen receptor module, three signaling modules, and a coreceptor module. These components convert information into instructions for the T cell to follow.\u00a0<\/span><\/p>\n

\u201cNow that we\u2019ve zeroed in on the building blocks that make up each module and the intricacies of how information is relayed through receptors and into the cell, there are even more opportunities to explore,\u201d Lee said.\u00a0<\/span><\/p>\n

\"\"
The illustration on the left represents a natural T cell, which was the inspiration behind the genetically engineered 5MCAR T cell, represented by the illustration on the right.<\/figcaption><\/figure>\n

Several CAR T cell therapies are approved by the Food and Drug Administration to treat blood cancers, including lymphomas, some forms of leukemia and multiple myeloma. Using nature as a blueprint, Kuhns engineered a biomimetic receptor called a\u00a0<\/span>five-module chimeric antigen receptor<\/b><\/a>, or\u00a0<\/span>5M<\/span>CAR, that can be added to T cells.<\/span><\/p>\n

Kuhns and Lee are testing their engineered\u00a0<\/span>5M<\/span>CAR T cells against Type 1 diabetes. In 2020, they co-authored a\u00a0<\/span>paper<\/b><\/a>\u00a0that described the\u00a0<\/span>5M<\/span>CAR T cell and its effectiveness against Type 1 diabetes in a nonobese diabetic mouse model.<\/span><\/p>\n

\u201cType 1 diabetes develops when overreactive immune cells infiltrate areas of the pancreas and kill beta cells. Beta cells are responsible for producing the blood sugar-regulating hormone insulin,\u201d Kuhns said. \u201cOur paper showed evidence that we can direct different immune cells to kill the overreactive immune cells. This stops the process before it really gets going.\u201d\u00a0<\/span><\/p>\n

They are encouraged by their findings. Lee\u2019s initial experiments at CAMI will test how updated versions of\u00a0<\/span>5M<\/span>CAR T cells might be able eliminate Type 1 diabetes after it has already developed.<\/span><\/p>\n

Lee and Kuhns are also collaborating on future generations of\u00a0<\/span>5M<\/span>CAR T cells they hope to advance to clinical trials. The ultimate goal, Lee says, is to develop a product to prevent and treat Type 1 diabetes in humans.\u00a0<\/span><\/p>\n

\u201cEngineering is an iterative process: you build, test, refine and repeat,\u201d Kuhns said. \u201cThat\u2019s why modern cars don\u2019t look anything like the Model A Fords built in 1903. We\u2019ll be doing the refining in my lab and then taking that work to CAMI, almost like a showroom floor.\u201d<\/span><\/p>\n

In addition to\u00a0<\/span>5M<\/span>CAR T cells, Kuhns and Lee are investigating CD4, a coreceptor that they found plays a more active role in regulating T cell receptor signaling than previously thought.<\/span><\/p>\n

In a study published in\u00a0<\/span>eLife<\/b><\/a>\u00a0in July 2022, they examined the relationship between CD4 and T cell function through years of evolution in fish, reptiles, marsupials and mammals. They discovered sequences of amino acids, called motifs, on different parts of CD4 that seemed to strengthen or weaken its signaling power.\u00a0<\/span><\/p>\n

\u201cThe CD4 molecule has been evolving these motifs for millions of years, so we knew they must be important,\u201d said Lee, who published a second paper about CD4 motifs in\u00a0<\/span>eLife<\/b><\/a>\u00a0in April. \u201cThis knowledge is likely to fuel future innovations.\u201d<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

People have been waiting a long time for a cure for Type 1 diabetes.\u00a0Hannah Pizzato, PhD, is one of them. Pizzato was diagnosed with Type 1 diabetes when she was 4 years old. She was too young to understand it is an autoimmune disease. She didn\u2019t know her immune system was attacking cells in her […]<\/p>\n","protected":false},"author":3,"featured_media":1936,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[24],"tags":[],"college":[],"uahs_theme":[],"class_list":["post-1933","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-cami"],"acf":[],"yoast_head":"\nCAMI scientists determined to develop new treatments for autoimmune diseases - University of Arizona Health Sciences Annual Impact Report 2024<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/annualreports.healthsciences.arizona.edu\/2024\/cami-scientists-determined-to-develop-new-treatments-for-autoimmune-diseases\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"CAMI scientists determined to develop new treatments for autoimmune diseases - University of Arizona Health Sciences Annual Impact Report 2024\" \/>\n<meta property=\"og:description\" content=\"People have been waiting a long time for a cure for Type 1 diabetes.\u00a0Hannah Pizzato, PhD, is one of them. 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