BOSTON—Attacking the immune response that causes insulin-dependent diabetes with a tuberculosis drug could lead to a new way of treating the disease, according to a new study conducted by scientists Massachusetts General Hospital (MGH) and Harvard Medical School.
In the study, published Sept. 9 in the Proceedings of National Academy of Sciences (PNAS), the researchers showed they can kill defective autoimmune cells that destroy insulin-producing islets in human blood cells with the use of bacillus Calmette-Guerin (BCG), a generic tuberculosis drug. The finding could hold the key to promising new therapies for type 1diabetes, the researchers say.
The research builds upon the groundbreaking research of Dr. Denise Faustman, director of Immunobiology at MGH East and an associate professor of medicine at Harvard, whose team has shown in several studies over the past decade that triggering the expression of the immune-system modulator tumor necrosis factor (TNF) in diabetic mice with the use of BCG, which temporarily elevates TNF levels, led to the death of the T cells responsible for destroying insulin-producing pancreatic islets. After receiving this treatment, the animals were able to regenerate healthy islet cells that produced normal levels of insulin, effectively curing the animals' diabetes.
The new study, however, is being credited as the first demonstration of this strategy in human cells and evidence of the viability of a clinical trial that is currently underway.
"The data in the paper clearly points to the pathway for new drug development for autoimmune diseases," Faustman says. "This is human data from autoimmune patients showing that just like a diversity of spontaneous animal models of autoimmunity, TNF can kill in a targeted way only auto reactive T cells in cultures. This is a step forward in the quest to avoid non-specific immune suppression for autoimmunity and opens up a whole new pathway for drug development."
Using T cells from more than 1,000 patients with type 1 diabetes, the researchers showed that blocking a metabolic pathway regulating the immune system specifically eliminated immune cells that react against a patient's own tissues. The team isolated highly pure CD4 or CD8 T cells from patients with type 1 diabetes, other autoimmune diseases and healthy controls.
Using two cell death assays, the team found that a subpopulation of CD8, but not CD4, T cells in patients' blood was vulnerable to TNF or TNF agonist-induced death. One agonist for the TNFR2 receptor exhibited a dose-response pattern of killing. In type 1 diabetes, the subpopulation of T cells susceptible to TNF or TNFR2 agonist-induced death was traced specifically to autoreactive T cells to insulin, a known autoantigen. Other activated and memory T cell populations were resistant to TNF-triggered death.
"This study shows that autoreactive T cells, although rare, can be selectively destroyed in isolated human blood. TNF and a TNFR2 agonist may offer highly targeted therapies, with the latter likely to be less systemically toxic," the researchers wrote.
The potential for BCG to reduce autoimmune T cells in patients with type 2 diabetes—established type 1 diabetes, not just new onset diabetes—has received Phase I approval by the FDA. Further testing will determine the optimal dose and timing of BCG administration, and the team hopes to be in a Phase II trial within 18 months, Faustman says.
"We want to get to the clinic as fast as possible," Faustman says. "This tuberculosis vaccine has an 80-year history of being the safest vaccine in the history of the world and can be used at low dose in vaccine form or high dose as a cancer treatment. This particular vaccine is known to elevate TNF, and it is a boost in TNF that kills the auto reactive T cells causing some forms of autoimmunity, i.e., diabetes."
The study, Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism, was co-authored by Liqin Ban, Jack Zhang, Limei Wang, Willem Kuhtreiber and Douglas Burger. DDN
In the study, published Sept. 9 in the Proceedings of National Academy of Sciences (PNAS), the researchers showed they can kill defective autoimmune cells that destroy insulin-producing islets in human blood cells with the use of bacillus Calmette-Guerin (BCG), a generic tuberculosis drug. The finding could hold the key to promising new therapies for type 1diabetes, the researchers say.
The research builds upon the groundbreaking research of Dr. Denise Faustman, director of Immunobiology at MGH East and an associate professor of medicine at Harvard, whose team has shown in several studies over the past decade that triggering the expression of the immune-system modulator tumor necrosis factor (TNF) in diabetic mice with the use of BCG, which temporarily elevates TNF levels, led to the death of the T cells responsible for destroying insulin-producing pancreatic islets. After receiving this treatment, the animals were able to regenerate healthy islet cells that produced normal levels of insulin, effectively curing the animals' diabetes.
The new study, however, is being credited as the first demonstration of this strategy in human cells and evidence of the viability of a clinical trial that is currently underway.
"The data in the paper clearly points to the pathway for new drug development for autoimmune diseases," Faustman says. "This is human data from autoimmune patients showing that just like a diversity of spontaneous animal models of autoimmunity, TNF can kill in a targeted way only auto reactive T cells in cultures. This is a step forward in the quest to avoid non-specific immune suppression for autoimmunity and opens up a whole new pathway for drug development."
Using T cells from more than 1,000 patients with type 1 diabetes, the researchers showed that blocking a metabolic pathway regulating the immune system specifically eliminated immune cells that react against a patient's own tissues. The team isolated highly pure CD4 or CD8 T cells from patients with type 1 diabetes, other autoimmune diseases and healthy controls.
Using two cell death assays, the team found that a subpopulation of CD8, but not CD4, T cells in patients' blood was vulnerable to TNF or TNF agonist-induced death. One agonist for the TNFR2 receptor exhibited a dose-response pattern of killing. In type 1 diabetes, the subpopulation of T cells susceptible to TNF or TNFR2 agonist-induced death was traced specifically to autoreactive T cells to insulin, a known autoantigen. Other activated and memory T cell populations were resistant to TNF-triggered death.
"This study shows that autoreactive T cells, although rare, can be selectively destroyed in isolated human blood. TNF and a TNFR2 agonist may offer highly targeted therapies, with the latter likely to be less systemically toxic," the researchers wrote.
The potential for BCG to reduce autoimmune T cells in patients with type 2 diabetes—established type 1 diabetes, not just new onset diabetes—has received Phase I approval by the FDA. Further testing will determine the optimal dose and timing of BCG administration, and the team hopes to be in a Phase II trial within 18 months, Faustman says.
"We want to get to the clinic as fast as possible," Faustman says. "This tuberculosis vaccine has an 80-year history of being the safest vaccine in the history of the world and can be used at low dose in vaccine form or high dose as a cancer treatment. This particular vaccine is known to elevate TNF, and it is a boost in TNF that kills the auto reactive T cells causing some forms of autoimmunity, i.e., diabetes."
The study, Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism, was co-authored by Liqin Ban, Jack Zhang, Limei Wang, Willem Kuhtreiber and Douglas Burger. DDN
