Monitoring soluble interleukin-2 receptor levels in related and unrelated donor allogeneic bone marrow transplantation

Abstract

Summary:Acute graft-versus-host disease (GVHD) is effected by donor T lymphocytes which have been stimulated by host antigens. Activated donor T lymphocytes express interleukin-2 receptor (IL-2R), which is comprised of three subunits (␣, ␤, ␥). During activation, the ␣ IL-2R subunit (CD25) is shed from the receptor complex and can be measured in the circulation. Soluble IL-2R␣ (sIL-2R) levels are increased in states of immune activation including GVHD, and could theoretically be used as a guide to therapy. Since IL-2R␣ expression is an early marker of T cell activation, we investigated: (1) if an increase in sIL-2R is specific for acute GVHD; and (2) if serial sIL-2R levels can identify patients with early GVHD, prior to the onset of clinical tissue damage (effector function). Weekly sIL-2R levels were monitored in 36 patients undergoing matched related (n ‫؍‬ 23) or matched unrelated (n ‫؍‬ 13) allogeneic bone marrow transplantation (BMT). There was no significant difference in sIL-2R levels between matched related and matched unrelated recipients. Patients with acute GVHD (n ‫؍‬ 19, 53%) demonstrated higher sIL-2R levels, than those without during weeks 2 and 3 post-BMT (P ‫؍‬ 0.02 and 0.04, Mann-Whitney U test, twotailed). In patients with acute GVHD, the rise in sIL-2R preceded the clinical signs of GVHD (16/19 patients). However, patients with sepsis demonstrated a trend towards higher sIL-2R levels at week 1 and significantly greater levels by week 4 (P = 0.02). Furthermore, patients with veno-occlusive disease (VOD) (25%) also had significantly higher sIL-2R levels at week 2 (P ‫؍‬ 0.03). We conclude that although sIL-2R levels increase in patients with acute GVHD, similar increases are seen in patients with VOD and/or sepsis and therefore, as a single biochemical marker, we find that serial measurements of sIL-2R lacks sufficient specificity to guide GVHD therapy.

Immunological reconstitution and correlation of circulating serum inflammatory mediators/cytokines with the incidence of acute graft-versus-host disease during the first 100 days following unrelated umbilical cord blood transplantation

“…Serum levels of soluble IL-2R (sIL-2R), although increased post UCBT within the first week, were not higher in patients with more severe aGVHD grade II-IV as compared to patients with grade 0-I aGVHD, and could not predict early onset of severe aGVHD. This finding was in contrast to what was reported by other investigators, 8,[35][36][37] who found a significant elevation of sIL-2R as early as 3 days 8 or up to 2 weeks 36 post allogeneic BMT in patients with aGVHD that correlated with the severity of aGVHD and returned to normal levels when aGVHD was clinically controlled.…”

Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease

“…Whether the sIL-2R level after HSCT is a good indicator of aGVHD remains unclear. 11,12,29 In the present study, there was a tendency to significance between a high sIL-2R level and the severity of aGVHD, but statistical significance was not established because the plasma sIL-2R level was increased in the patients with an infection. TNF-␣ and IFN-␥ were thought to be an effector cytokine for the development of GVHD, but no definite peak of either cytokine could be found in plasma samples obtained after HSCT in our study.…”

“…7,10 Elevation of serum soluble IL-2 receptor (sIL-2R) has been found in GVHD, veno-occlusive disease and infection. 11,12 IL-6 is also involved in the development of GVHD and infections following bone marrow transplantation (BMT). [13][14][15] Furthermore, tumor necrosis factor (TNF)-␣, interferon (IFN)-␥ and IL-15 were reported to be involved in the development of GVHD.…”

Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease

“…16 However, numerous candidate GVHD biomarkers have been studied during the past years, almost all of them belonging to the cytokine cascades driving GVHD effector cells, such as gammainterferon and the soluble form of its receptor, sTNF-R, interleukin 6 (IL-6), IL-8, IL-18, ICAM-1, IL-1, IL-10, IL-12, IL-2, IL-4, and-investigated best-soluble interleukin-2 receptor (sIL2-R, sCD25). [17][18][19][20][21][22][23][24] Although in particular sCD25 and IL-18 showed some association with (acute) GVHD, lack of specificity 18,19,25 and poor correlation to GVHD intensity 26 have precluded their routine use for GVHD monitoring either alone or in the context of multifactorial grading systems.…”