IL-2 therapy restores immune tolerancein graft-versus-host disease
medwireNews: Daily administration of interleukin (IL)-2 can restore the homeostasis of CD4+Foxp3+ regulatory T cells (Tregs) and promote immune tolerance in patients with graft-versus-host disease (GVHD), report researchers.
In a study of 45 patients who underwent hematopoietic stem cell transplantation, low-dose IL-2 therapy induced alterations in Treg homeostasis among those with severe chronic GVHD, report Jerome Ritz (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and colleagues. The changes included increased Treg proliferation and thymic export, as well as an enhanced resistance to apoptosis.
"These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4+ T cell subsets and promotes the reestablishment of immune tolerance," writes the team in Science Translational Medicine.
Firstly, the researchers found that when the absolute numbers of CD4 T cells were considered, the IL2/CD4, IL-7/CD4, and IL-15/CD4 T cell ratios were substantially increased in those with severe chronic GVHD compared with those without GVHD.
CD4 T cell subset analyses showed that the degree of phosphorylation of signal transducer and activator of transcription 5 (pStat5) in Tregs and conventional CD4 T cells (Tcons) was similar between those with no, mild, or moderate chronic GVHD, but was increased in Tcons among those with severe chronic GVHD. Furthermore, the T reg-pStat5/T con-pStat5 ratio steadily decreased with increasing GVHD severity.
The team then examined 14 patients with refractory chronic GVHD who had been enrolled in a trial of 8-week daily low-dose IL-2 therapy. One week after treatment inititiaton, pStat5 significantly increased in Tregs whereas it decreased in Tcons, resulting in a significant increase in the Treg-pStat5/Tcon-pStat5 ratio at this timepoint.
However, this high level of pStat5 in Tregs was not sustained with ongoing treatment and after 2 weeks pStat5 levels reached their lowest level in both Tregs and Tcons. Interestingly, pStat5 levels in both subsets then gradually increased but the ratio of Treg-pStat5/Tcon-pStat5 was similar to that found in individuals without GVHD.
"These findings indicate that exogenous low dose IL-2 corrected the balance of Treg and Tcon activation in patients with chronic GVHD, and this was maintained for the duration of therapy," say Ritz et al.
Analysis of the functional effects of IL-2 therapy on Treg homeostasis showed that IL-2 therapy induced a rapid increase in Treg proliferation that peaked one week after treatment but returned to baseline levels as the number of circulating Tregs increased and IL-2 levels decreased.
In addition, markers of recent thymic emigrants (RTEs) indicated that while IL-2 did not increase levels of Tcon RTE, it significantly increased Treg-RTE, which peaked at 4 weeks and remained high 4 weeks after IL-2 therapy was discontinued.
Finally, the team found that Bcl-2 expression, a marker of apoptosis inhibition, significantly increased during IL-2 therapy and that it was significantly greater in Tregs than in Tcons.
"Considering the restoration of normal Treg homeostasis during GVHD, low-dose IL-2 may provide a new strategy for restoration of immune tolerance in other clinical settings characterized by Treg deficiency," notes the team.
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By Sally Robertson, medwireNews Reporter