Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival

Abstract

Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graftversus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T-and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P ‫؍‬ .003) and after a reducedintensity conditioning regimen (P ‫؍‬ .03). Low posttransplantation iNKT/T ratios (ie, < 10 ؊3 ) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P ‫؍‬ .001). Inversely, reaching iNKT/T ratios > 10 ؊3 before day 90 was associated with reduced nonrelapse mortality (P ‫؍‬ .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P ‫؍‬ .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 ؋ 10 ؊3 was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival. (Blood. 2012;120(10):2144-2154)

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…[133] In patients, early posttransplant recovery of donor-derived iNKT cells after alloHSCT has been associated with reduced risk of aGVHD. [45] Accordingly, high content of iNKT cells in the stem cell graft has also been associated with a reduced risk of aGVHD. [127] Thus, expanding iNKT (by in vivo or ex vivo manipulations) might provide a new potential approach for controlling GVHD.…”

GVHD protection? ThiNK iNKT cells

“…9 The present study by Rubio and colleagues extends these findings by examining iNKT recovery in 71 recipients of allogeneic HSCT in relation to clinical outcomes, including the incidence of GVHD, relapse, and overall survival. 1 Strikingly, the ratio of iNKT cells to other T cells, when higher than 1:1000, remained a predictor of lower GVHD incidence, even after multivariate modeling. 1 Subsets of patients with a high iNKT:T ratio were found to have reduced nonrelapse mortality rates and a higher actuarial probability of overall survival.…”

“…1 Strikingly, the ratio of iNKT cells to other T cells, when higher than 1:1000, remained a predictor of lower GVHD incidence, even after multivariate modeling. 1 Subsets of patients with a high iNKT:T ratio were found to have reduced nonrelapse mortality rates and a higher actuarial probability of overall survival. In a small subset of patients, iNKT cells were isolated and expanded, demonstrating the ability of these cells to produce expected cytokines, including IFN␥ and IL-4.…”

“…1 Like regulatory T cells, iNKT cells are a T-cell subset that is found in mice and in humans, and appear to be capable of controlling autoimmunity and alloreactivity in models of disease, including GVHD. As recently reviewed by Berzins et al, 4 these cells are distinct from most peripheral T cells in that they express an invariant T-cell receptor (V␣24-J␣18 in humans), are selected by the nonclassical HLA molecule CD1d, and can be activated by glycolipids such as ␣-galactosylceramide.…”

“…1 A llogeneic hematopoietic stem cell transplantation (HSCT) remains the best curative therapy for many patients with hematologic malignancies and/or marrow failure states. While significant advances in transplant conditioning and supportive care have resulted in a dramatic decrease in early mortality and have facilitated an expansion in the application of HSCT worldwide, significant challenges remain.…”