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Method could prevent GVHD while preserving GVL effect


 

Image from PLOS ONE

Micrograph showing GVHD

Researchers believe they have found a way to prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT) while preserving a strong graft-versus-leukemia (GVL) effect.

In experiments with mice, the team found that temporary in vivo depletion of CD4+ T cells soon after HSCT prevented GVHD without inhibiting GVL effects.

The depletion of CD4+ cells essentially caused CD8+ cells to become exhausted in their quest to destroy normal tissue but strengthened in their fight against leukemia, which meant the CD8+ cells could eliminate leukemic cells without causing GVHD.

Defu Zeng, MD, of City of Hope in Duarte, California, and his colleagues recounted these findings in the Journal of Clinical Investigation.

The researchers were able to achieve temporary in vivo depletion of CD4+ T cells by injecting mice with an anti-CD4 monoclonal antibody (mAb).

The team found that a single injection of the mAb given immediately after HSCT prevented acute but not chronic GVHD. Three injections of the mAb—given on days 0, 14, and 28—prevented both types of GVHD.

The researchers said their results suggest GVHD is more effectively prevented by temporary in vivo depletion of donor CD4+ T cells early after HSCT than by ex vivo depletion of donor CD4+ T cells.

This is because treatment with an anti-CD4 mAb temporarily depletes both the injected mature CD4+ T cells and the CD4+ T cells generated de novo from the marrow progenitors early after HSCT.

In explaining the mechanism behind their observations, the researchers noted that the interaction between PD-L1 and CD80 has been shown to exacerbate GVHD, but costimulation of CD80 and PD-1 ameliorates GVHD.

In their experiments, the team found that depleting CD4+ T cells increased serum IFN-γ and reduced IL-2 concentrations. And this led to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells.

The researchers said that, in GVHD target tissues, the interactions of PD-L1 and PD-1 on donor CD8+ T cells caused anergy, exhaustion, and apoptosis. These effects prevented the development of GVHD.

On the other hand, in lymphoid tissues, the interactions of PD-L1 and CD80 augmented CD8+ T-cell expansion without increasing anergy, exhaustion, or apoptosis. This allowed for the preservation of GVL effects.

“If successfully translated into clinical application, this [CD4+ T-cell-depleting] regimen may represent one of the novel approaches that allow strong GVL effects without causing GVHD,” Dr Zeng said.

“This kind of regimen has the potential to promote widespread application of allogenic [HSCT] as a curative therapy for hematological malignancies.”

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