New strategy addresses the fatal autoimmune disease with no outward effects off-target -
In a study that could have important implications for the future treatment of auto- immunity and related conditions, scientists at the Perelman School of Pennsylvania University of medicine found a way to remove the subset of making antibody-producing cells that cause autoimmune disease without harming the rest the immune system. The autoimmune disease of the team studied is called pemphigus vulgaris (PV), a condition in which specific immune cells from a patient attack a protein called DSG3 (Dsg3) that normally adheres the skin cells.
Current treatments of autoimmune disease, such as prednisone and rituximab, remove much of the immune system, leaving patients vulnerable to opportunistic infections and potentially deadly cancers.
The Penn researchers demonstrated their new technique in dealing successfully autoimmune disease otherwise fatal in a mouse model without apparent off-target effects, which could harm healthy tissue. The results are published in an online document First release in science.
"This is an effective strategy to target the autoimmune cells and sparing just good immune cells that protect us against infection," said co-lead author Aimee S. Payne, MD, PhD, Albert M. Kligman Associate Professor of Dermatology.
Payne and co-senior author Michael C. Milone, MD, PhD, assistant professor of pathology and laboratory medicine, adapted the technique of the strategy against the promising cancer by which cells T are designed to destroy malignant cells in certain leukemias and lymphomas.
"Our study effectively opens the application of this anti-cancer technology for the treatment of a wide wider range of diseases, including autoimmunity and transplant rejection," said Milone .
the key element of the new strategy is based on a target receptor recognizing artificial called chimeric antigen receptor, or CAR, which can be engineered into the patient's T cells. in human trials , researchers remove some of the patient's T cells by a process similar to dialysis, then engineer in a laboratory to add the CAR gene so that the new receptor is expressed in T cells the new cells are then multiplied in the . lab before re-infusion into the patient T cells use their CAR receptors to bind to molecules on the target cells, and the act of binding initiates an internal signal that strongly activates T cells -. So they quickly destroy their targets
The RCA base T cell concept was first described in the late 1980s, primarily as a strategy against cancer, but the technical challenges delayed its translation into successful therapies. Since 2011, however, the experimental CAR T cell treatments for leukemia and B cell lymphomas - cancers in which healthy B cells of patients become cancerous -. Have been successful in some patients for whom all standard treatments failed
B cells that produce antibodies, can also cause autoimmunity. Payne autoimmunity research, and a few years ago, a postdoctoral researcher in his lab, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against autoimmune diseases B cells Soon the laboratory Payne teamed with Milone, who studies CAR T cells technology, hoping to find a powerful new way to treat these conditions.
"We thought we could adapt this technology which is really good to kill all the B cells of the body to specifically target B cells that make antibodies that cause autoimmune diseases," said Milone.
"target only the cells that cause autoimmunity was the ultimate goal of therapy in this area," noted Payne.
A more specific receptor disease
in the new study, which Ellebrecht was the first author, the team aims to pemphigus vulgaris. This condition occurs when antibodies from a patient attack the molecules that normally prevent cells skin together. When untreated, PV led to extensive blistering of the skin and is almost always fatal, but in recent decades, the condition was treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil and rituximab.
To treat PV without causing broad immunosuppression, the Penn team designed an artificial RCA receiver who would lead the patient's T cells to attack only the harmful B cells producing anti-Dsg3 antibodies.
the team developed a "chimeric receptor autoantibody," or SRL, which shows fragments of Dsg3 of autoantigen - the same fragments for which PV causing antibodies and B cells generally bind in as laboratory and other Payne demonstrated in previous studies. Acts of artificial receptors as a decoy for B cells that target Dsg3, putting them in touch with fatal therapeutic T cells.
many variations Test, the team finally found an artificial receptor design worked well in cell culture, enabling T cells to effectively destroy host cells producing antibodies to Desmoglein, including from PV patients. The modified T cells also successfully performed in a murine model of PV, kill specific cells Desmoglein B and preventing the formation of blisters and other manifestations of autoimmunity in animals.
"We were able to demonstrate that the treatment killed all Dsg3 specific B cells, a proof of concept that this approach works," said Payne.
T cell therapies can be complicated by many factors. But, in these experiments, the cells modified by the Penn scientists have retained their activity despite the presence of anti-Dsg3 antibodies that have spread their artificial receptors. Furthermore, there was no sign that the modified T cells caused side effects by hitting the wrong target cell in mice.
The team now plans to test their treatment in dogs, which can also develop PV and often die of the disease. "If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in humans pemphigus patients," said Payne .
Also on the horizon for the Penn scientists are applications SRL T-cell technology to other types of autoimmunity. Immune rejection complicating organ transplants, and normally requires immunosuppressive therapy long-term medication, may also be treated with cellular technology T. SRL
"If you can identify a specific marker of B cell that you want to target, then, in principle, this strategy can work, "said Payne.
Current treatments of autoimmune disease, such as prednisone and rituximab, remove much of the immune system, leaving patients vulnerable to opportunistic infections and potentially deadly cancers.
The Penn researchers demonstrated their new technique in dealing successfully autoimmune disease otherwise fatal in a mouse model without apparent off-target effects, which could harm healthy tissue. The results are published in an online document First release in science.
"This is an effective strategy to target the autoimmune cells and sparing just good immune cells that protect us against infection," said co-lead author Aimee S. Payne, MD, PhD, Albert M. Kligman Associate Professor of Dermatology.
Payne and co-senior author Michael C. Milone, MD, PhD, assistant professor of pathology and laboratory medicine, adapted the technique of the strategy against the promising cancer by which cells T are designed to destroy malignant cells in certain leukemias and lymphomas.
"Our study effectively opens the application of this anti-cancer technology for the treatment of a wide wider range of diseases, including autoimmunity and transplant rejection," said Milone .
the key element of the new strategy is based on a target receptor recognizing artificial called chimeric antigen receptor, or CAR, which can be engineered into the patient's T cells. in human trials , researchers remove some of the patient's T cells by a process similar to dialysis, then engineer in a laboratory to add the CAR gene so that the new receptor is expressed in T cells the new cells are then multiplied in the . lab before re-infusion into the patient T cells use their CAR receptors to bind to molecules on the target cells, and the act of binding initiates an internal signal that strongly activates T cells -. So they quickly destroy their targets
The RCA base T cell concept was first described in the late 1980s, primarily as a strategy against cancer, but the technical challenges delayed its translation into successful therapies. Since 2011, however, the experimental CAR T cell treatments for leukemia and B cell lymphomas - cancers in which healthy B cells of patients become cancerous -. Have been successful in some patients for whom all standard treatments failed
B cells that produce antibodies, can also cause autoimmunity. Payne autoimmunity research, and a few years ago, a postdoctoral researcher in his lab, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against autoimmune diseases B cells Soon the laboratory Payne teamed with Milone, who studies CAR T cells technology, hoping to find a powerful new way to treat these conditions.
"We thought we could adapt this technology which is really good to kill all the B cells of the body to specifically target B cells that make antibodies that cause autoimmune diseases," said Milone.
"target only the cells that cause autoimmunity was the ultimate goal of therapy in this area," noted Payne.
A more specific receptor disease
in the new study, which Ellebrecht was the first author, the team aims to pemphigus vulgaris. This condition occurs when antibodies from a patient attack the molecules that normally prevent cells skin together. When untreated, PV led to extensive blistering of the skin and is almost always fatal, but in recent decades, the condition was treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil and rituximab.
To treat PV without causing broad immunosuppression, the Penn team designed an artificial RCA receiver who would lead the patient's T cells to attack only the harmful B cells producing anti-Dsg3 antibodies.
the team developed a "chimeric receptor autoantibody," or SRL, which shows fragments of Dsg3 of autoantigen - the same fragments for which PV causing antibodies and B cells generally bind in as laboratory and other Payne demonstrated in previous studies. Acts of artificial receptors as a decoy for B cells that target Dsg3, putting them in touch with fatal therapeutic T cells.
many variations Test, the team finally found an artificial receptor design worked well in cell culture, enabling T cells to effectively destroy host cells producing antibodies to Desmoglein, including from PV patients. The modified T cells also successfully performed in a murine model of PV, kill specific cells Desmoglein B and preventing the formation of blisters and other manifestations of autoimmunity in animals.
"We were able to demonstrate that the treatment killed all Dsg3 specific B cells, a proof of concept that this approach works," said Payne.
T cell therapies can be complicated by many factors. But, in these experiments, the cells modified by the Penn scientists have retained their activity despite the presence of anti-Dsg3 antibodies that have spread their artificial receptors. Furthermore, there was no sign that the modified T cells caused side effects by hitting the wrong target cell in mice.
The team now plans to test their treatment in dogs, which can also develop PV and often die of the disease. "If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in humans pemphigus patients," said Payne .
Also on the horizon for the Penn scientists are applications SRL T-cell technology to other types of autoimmunity. Immune rejection complicating organ transplants, and normally requires immunosuppressive therapy long-term medication, may also be treated with cellular technology T. SRL
"If you can identify a specific marker of B cell that you want to target, then, in principle, this strategy can work, "said Payne.
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