Immune Reactions Following Reduced-Intensity Allogeneic Stem Cell Transplantation (Allo-CST): Role of Plasma IL-7 and IL-15 Levels, and Their Receptors

Abstract 1251

Allogeneic stem cell transplantation (allo-SCT) following reduced-intensity conditioning (RIC) represents a concrete alternative to standard myeloablative conditioning. Even though, immune reactions observed after RIC (i.e. GVHD, GVL.), tend to be similar to those observed after myeloablative regimens, there are many differences in their clinical features, timing of onset, and their impact on patient's outcome. The homeostatic cytokines, IL-7 and IL-15 are essential driving forces for homeostatic peripheral expansion of T lymphocytes that are responsible, not only for GVL effect but also for GVHD which is a major complication post-transplant. Almost all mature T-cells express the specific IL-7 receptor alpha chain (IL-7Rα). Memory CD8⁺ T cells and natural killer (NK) cells express the highest levels of IL-2/15Rβ chain, making these cells particularly responsive to IL-15.

Few studies have associated GVHD with systemic levels of either IL-7 or IL-15 but only one concerned patients undergoing RIC. However, patients reported in the latter study, had received prior induction chemotherapy and experienced profound lymphopenia after conditioning, leading to levels of IL-7 and IL-15 comparable to those usually observed after myeloablative regimens. In addition, the issue of IL-7R and IL-2/15Rβ expression has not been addressed yet in allo-SCT patients. This prompted us to prospectively investigate plasma levels of IL-7 and IL-15, T-cell recovery, and the expression levels of IL-7Rα and IL-2/15Rβ chains in patients undergoing RIC.

Forty-five consecutive patients who underwent fully HLA-matched allo-SCT after RIC were included. Plasma levels of IL-7 and IL-15 were determined by ELISA at enrolment, on day 0 before grafting, every three days during the first month, and then on days 60 and 90. CD3⁺, CD4⁺, CD8⁺ T-cells and NK cells counts at day 30, 60 and 90 post-graft were obtained by flow-cytometry-based technique. Expression of IL-7Rα and IL-2/15Rβ (% and MFI) was evaluated on each subsets of naïve and memory T-cells, categorized according to their expression of CD45RA and CCR7 markers.

Kinetic courses of plasma IL-7 levels, evolved inversely to lymphocyte counts up to day 30 (R= -.529; P= .001). The higher plasma IL-7 levels were associated with the lower MFI of IL-7Rα on CD4+ naïve, CD8+ naïve, CD4+ central memory, and CD8+ central memory T-cells (p=.005, .01, <.001 and .005, respectively). IL-15 levels peaked on day +7 to rapidly return to a normal range. No statistically significant correlation was found between IL-15 levels and the expression of IL-2/15Rβ. A positive correlation was evidenced between IL-15 and CRP levels on day +7 (R= .488; P = .013) and day +14 (R= .621; P< .001) while the correlation between IL-7 and CRP levels at the same time points reached marginal statistical significance.

A total of 16 (35%) recipients developed grades 2–4 acute GVHD (aGVHD) at a median time of 42 days post graft. By day +30, IL-7 and IL-15 levels were slightly correlated with aGVHD grades (R=.30; P=.05 and R=.31; P = .048, respectively) and inversely correlated with the time to onset (IL-7: R= -.334; P= .031 and IL-15: R= -.367; P= .018). In those patients, there was a diminished surface densities of IL-7Rα chain in both the naïve (P= .029) and the central memory (P= .043) CD4⁺ T-cells. In multivariate analysis, IL-7 level measured on day +30 was the foremost predictive factor for grade 2–4 aGVHD (P= .002).

Collectively, this study indicates that the level of IL-7 depends rather on the level of lymphopenia whereas IL-15 is more sensitive to the inflammatory context. A high level of IL-7 induces a downregulation of IL-7Rα on naïve and central memory CD4⁺ T cells, already known to contain alloreactive T cells. The determination of plasma level of IL-7 by day+30 would help predict aGVHD. This predictive time is less precocious than those observed after myeloablative conditioning in agreement with the later development of aGVHD observed with RIC regimens.