Treg restoration important following HSCT

Regulatory T cells

A recent study found that CD4⁺CD25⁺Foxp3⁺ Tregs play a vital role in maintaining the immune system’s tolerance following allogeneic hematopoietic stem cell transplant (HSCT).

A team of researchers, led by Jerome Ritz, MD, at Dana-Farber Cancer Institute in Boston, looked at patients who underwent allogeneic HSCT after myeloablative conditioning and standard immunosuppressive regimens for graft-versus-host-disease (GVHD) prophylaxis and found that CD4⁺ lymphopenia plays a major role in Treg homeostasis. A long-term imbalance after HSCT can result in a loss of tolerance and significant disease manifestations.

The study consisted of 78 patients who had never received allogeneic or autologous stem cell transplants. Each was considered standard risk if they had acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in first remission, chronic myelogenous leukemia (CML) in chronic phase, or myelodysplastic syndromes (MDS) with refractory anemia (RA), or RA with ringed sideroblasts (RARS). All other patients were considered high-risk.

The initial study included 33 patients and focused on the reconstitution of Tregs within the first year after HSCT. The team gathered samples a median of 9 months after transplant and Tregs were compared to conventional CD4⁺ T cells (Tcons) in the same patient samples.

After transplant, thymic generation of naïve Tregs was noticeably impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. Tregs underwent higher levels of proliferation than Tcons in response to CD4⁺ lymphopenia after HSCT, but Tregs undergoing homeostatic proliferation also showed an increase in susceptibility to Fas-mediated apoptosis.

Tregs rapidly expanded and achieved normal levels by 9 months following HSCT. However, they declined in patients with prolonged CD4⁺ lymphopenia. The decline in Tregs resulted in a relative deficiency of Tregs, which was associated with a high incidence of GVHD.

The researchers also prospectively monitored lymphocyte reconstitution in a separate group of 45 of the patients. They categorized the patients according to whether their CD4⁺ T-cell counts at 6 months posttransplant were more or less than 260/μL.

In patients with higher T-cell counts, Tcon and Treg levels increased gradually over the 2-year observation period, and patients were able to achieve normal levels.

In patients with lower T-cell counts, Tcons increased gradually, but they never achieved normal levels. Tregs increased in the first 9 months after HSCT, but subsequently declined with persistent lymphopenia. At 24 months posttransplant, their Treg levels remained very low.

And 29% of those who recovered their T-cell subsets developed extensive chronic GVHD, compared to 77% of those patients with persistent CD4⁺ lymphopenia.

From the study, the team concluded that CD4⁺ lymphopenia is a critical factor in Treg homeostasis and that a prolonged imbalance can result in loss of tolerance and significant clinical disease manifestation.

Their findings were published in the April 12 issue of the Journal of Clinical Investigation.