New Model Proposed for Maintenance of GVHD

By Dustin Samples - Last Updated: May 17, 2023

Graft-versus-host disease (GVHD) is a condition that occurs after an allogeneic stem cell transplant (SCT) where the donor T-cells attack the recipient’s tissue. It can happen immediately (acute GVHD, within the first 100 days) or weeks to months after the SCT (chronic GVHD). Both types can occur in different locations in the body and have devastating effects on the patient.

Stem cell transplant recipients are placed on strong immunosuppressant drugs leading up to and after the transplant for GVHD treatment and prophylaxis. The hope is that these drugs will stop the recruitment of recipient T-cells in the battle against recipient tissue. Despite strong immunotherapy that leaves recipients susceptible to infections, GVHD often persists. Researchers at the University of Pittsburgh School of Medicine now think they know why.

According to their paper published earlier this year in Immune, recipient T-cells aren’t recruited from the blood. Instead, donor T-cells maintain a separate colony in the infected tissue without relying on new T-cells from the blood. It should be noted that while the study results are compelling, the team used a mouse model and has yet to demonstrate their results in humans.

The study’s authors tracked a specific T-cell population from the donor to the recipient. They found that a “pool” of donor cells, a TCF-1+ population, remained in the tissues affected by GVHD that “preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer.”

“A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation,” lead author Faruk Sacirbegovic wrote. The answer seems a bit more clear due to this research.

“We think that progenitor T cells are long-lived in target tissues and are critical for maintaining GVHD,” Sacirbegovic said of his study in an interview with Science Daily, adding, “After the initial seeding phase, the disease is mostly sustained within the tissue itself without a lot of input from new T cells in the blood.”

While this research is translational in nature and has yet to be demonstrated in humans, the possibility that GVHD is maintained locally in the affected tissue presents new treatment opportunities, such as targeting immunosuppression of the affected site or the specific T-cell subpopulation rather than the whole body. This could lead to lower toxicity and better immune system function in turn.

Speaking to Science Daily, senior study author Warren Shlomchik summarized, “Now that we know the identity of progenitor cells, we might be able to prevent them forming early post-transplant or target them directly after they’ve formed.”

References

Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells

Study reframes understanding of graft-versus-host disease

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