MicroRNAs required for cGVHD development

Photo by Aaron Logan

New research suggests a family of microRNAs, miR-17-92, plays a key role in chronic graft-versus-host disease (cGVHD).

Researchers found miR-17-92 is responsible for the T- and B-cell pathogenicity that causes cGVHD.

The team also discovered that pharmacological inhibition of miR-17 alleviated the symptoms of cGVHD in mice.

Yongxia Wu, PhD, of the Medical University of South Carolina in Charleston, and her colleagues reported these findings in Blood.

The researchers previously found that miR-17-92 regulates CD4 T-cell proliferation and Th1 and Treg differentiation in acute (a) GVHD.

So the team set out to investigate whether miR-17-92 regulates T- and B-cell differentiation and function in the development of cGVHD.

“Chronic GVHD has a different pathophysiology and different target organs than aGVHD,” Dr Wu noted. “It’s been a big challenge to try to find a target for cGVHD therapies because of the more complex immune reaction in cGVHD and the fact that its cellular and molecular mechanisms are not as well understood.”

“We decided to extend our aGVHD study to cGVHD, but there’s no single, well-defined murine model that can reflect all of the clinical manifestations seen in cGVHD patients. So we decided to study 4 different cGVHD models to best understand how miR-17-92 contributes overall, across many clinical presentations.”

The team performed a series of experiments in murine models of cGVHD after allogeneic bone marrow transplant (BMT). This included models of scleroderma that had transitioned from aGVHD to cGVHD, classic cGVHD scleroderma, lung inflammation, and a lupus-like condition.

The experiments revealed shared mechanisms by which miR-17-92 mediates cGVHD progression—namely, by regulating T helper-cell differentiation, B-cell activation, germinal center responses, and autoantibody production.

“The mechanism for how miR-17-92 regulates T and B cells was very consistent,” Dr Wu said. “In other words, we did not find any big differences among the models.”

The researchers also assessed whether pharmacological inhibition of miR-17 or miR-19—“key members in the miR-17-92 cluster”—might be effective in the treatment of cGVHD.

The team tested antagomirs specific for miR-17 or miR-19 in the scleroderma cGVHD model and the lupus-like condition.

Anti-miR-17, but not anti-miR-19, reduced skin damage in the scleroderma model and alleviated proteinuria in the lupus-like condition.

“So we not only found a new mechanism for cGVHD development by demonstrating that miR-17-92 is heavily involved in the T- and B-cell responses that lead to cGVHD, but we also found that blocking miR-17 substantially reduced cGVHD symptoms in mice,” Dr Wu said.

“That’s exciting because it provides strong evidence that this miR may be a good target for controlling cGVHD after allogeneic BMT.”

Now, Dr Wu and her colleagues are investigating how other microRNAs may be involved in regulating T- and B-cell function during allogeneic BMT.

Photo by Aaron Logan

New research suggests a family of microRNAs, miR-17-92, plays a key role in chronic graft-versus-host disease (cGVHD).

Researchers found miR-17-92 is responsible for the T- and B-cell pathogenicity that causes cGVHD.

The team also discovered that pharmacological inhibition of miR-17 alleviated the symptoms of cGVHD in mice.

Yongxia Wu, PhD, of the Medical University of South Carolina in Charleston, and her colleagues reported these findings in Blood.

The researchers previously found that miR-17-92 regulates CD4 T-cell proliferation and Th1 and Treg differentiation in acute (a) GVHD.

So the team set out to investigate whether miR-17-92 regulates T- and B-cell differentiation and function in the development of cGVHD.

“Chronic GVHD has a different pathophysiology and different target organs than aGVHD,” Dr Wu noted. “It’s been a big challenge to try to find a target for cGVHD therapies because of the more complex immune reaction in cGVHD and the fact that its cellular and molecular mechanisms are not as well understood.”

“We decided to extend our aGVHD study to cGVHD, but there’s no single, well-defined murine model that can reflect all of the clinical manifestations seen in cGVHD patients. So we decided to study 4 different cGVHD models to best understand how miR-17-92 contributes overall, across many clinical presentations.”

The team performed a series of experiments in murine models of cGVHD after allogeneic bone marrow transplant (BMT). This included models of scleroderma that had transitioned from aGVHD to cGVHD, classic cGVHD scleroderma, lung inflammation, and a lupus-like condition.

The experiments revealed shared mechanisms by which miR-17-92 mediates cGVHD progression—namely, by regulating T helper-cell differentiation, B-cell activation, germinal center responses, and autoantibody production.

“The mechanism for how miR-17-92 regulates T and B cells was very consistent,” Dr Wu said. “In other words, we did not find any big differences among the models.”

The researchers also assessed whether pharmacological inhibition of miR-17 or miR-19—“key members in the miR-17-92 cluster”—might be effective in the treatment of cGVHD.

The team tested antagomirs specific for miR-17 or miR-19 in the scleroderma cGVHD model and the lupus-like condition.

Anti-miR-17, but not anti-miR-19, reduced skin damage in the scleroderma model and alleviated proteinuria in the lupus-like condition.

“So we not only found a new mechanism for cGVHD development by demonstrating that miR-17-92 is heavily involved in the T- and B-cell responses that lead to cGVHD, but we also found that blocking miR-17 substantially reduced cGVHD symptoms in mice,” Dr Wu said.

“That’s exciting because it provides strong evidence that this miR may be a good target for controlling cGVHD after allogeneic BMT.”

Now, Dr Wu and her colleagues are investigating how other microRNAs may be involved in regulating T- and B-cell function during allogeneic BMT.

Photo by Aaron Logan

New research suggests a family of microRNAs, miR-17-92, plays a key role in chronic graft-versus-host disease (cGVHD).

Researchers found miR-17-92 is responsible for the T- and B-cell pathogenicity that causes cGVHD.

The team also discovered that pharmacological inhibition of miR-17 alleviated the symptoms of cGVHD in mice.

Yongxia Wu, PhD, of the Medical University of South Carolina in Charleston, and her colleagues reported these findings in Blood.

The researchers previously found that miR-17-92 regulates CD4 T-cell proliferation and Th1 and Treg differentiation in acute (a) GVHD.

So the team set out to investigate whether miR-17-92 regulates T- and B-cell differentiation and function in the development of cGVHD.

“Chronic GVHD has a different pathophysiology and different target organs than aGVHD,” Dr Wu noted. “It’s been a big challenge to try to find a target for cGVHD therapies because of the more complex immune reaction in cGVHD and the fact that its cellular and molecular mechanisms are not as well understood.”

“We decided to extend our aGVHD study to cGVHD, but there’s no single, well-defined murine model that can reflect all of the clinical manifestations seen in cGVHD patients. So we decided to study 4 different cGVHD models to best understand how miR-17-92 contributes overall, across many clinical presentations.”

The team performed a series of experiments in murine models of cGVHD after allogeneic bone marrow transplant (BMT). This included models of scleroderma that had transitioned from aGVHD to cGVHD, classic cGVHD scleroderma, lung inflammation, and a lupus-like condition.

The experiments revealed shared mechanisms by which miR-17-92 mediates cGVHD progression—namely, by regulating T helper-cell differentiation, B-cell activation, germinal center responses, and autoantibody production.

“The mechanism for how miR-17-92 regulates T and B cells was very consistent,” Dr Wu said. “In other words, we did not find any big differences among the models.”

The researchers also assessed whether pharmacological inhibition of miR-17 or miR-19—“key members in the miR-17-92 cluster”—might be effective in the treatment of cGVHD.

The team tested antagomirs specific for miR-17 or miR-19 in the scleroderma cGVHD model and the lupus-like condition.

Anti-miR-17, but not anti-miR-19, reduced skin damage in the scleroderma model and alleviated proteinuria in the lupus-like condition.

“So we not only found a new mechanism for cGVHD development by demonstrating that miR-17-92 is heavily involved in the T- and B-cell responses that lead to cGVHD, but we also found that blocking miR-17 substantially reduced cGVHD symptoms in mice,” Dr Wu said.

“That’s exciting because it provides strong evidence that this miR may be a good target for controlling cGVHD after allogeneic BMT.”

Now, Dr Wu and her colleagues are investigating how other microRNAs may be involved in regulating T- and B-cell function during allogeneic BMT.