Adoptive therapy by transfusing expanded donor murine natural killer T cells can suppress acute graft‐versus‐host disease in allogeneic bone marrow transplantation

Abstract

The results suggest that donor iNKT cells could alleviate GVHD symptoms and prolong survival after MHC-mismatched allogeneic BMT, which may be associated with the maintenance in IL-4 levels. These findings indicate that the therapy based on iNKT cells from MHC-mismatched donors has great potential in protection against GVHD after allogeneic hematopoietic stem cell transplantation.

Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

“…Study of iNKT cells in donor PBSC grafts provides a unique opportunity to accurately identify and enumerate iNKT cells as well as other effector and regulatory immune cells in humans and thus define their role in aGVHD, a major source of morbidity and mortality in allogeneic HSCT. We addressed this important question by studying the effect of iNKT cells contained in G-CSF-mobilized PBSC grafts on the basis of evidence from the murine model showing that (1) G-CSF-mobilized iNKT cells protect from aGVHD and enhance the GVL effect 14 and (2) adoptively transferred, unmanipulated, 17 or in vitro ␣GC-expanded 15,16 iNKT cells can ameliorate aGVHD.…”

“…To directly show that human iNKT cells are able to inhibit the alloresponse, as shown in murine studies in which ␣GC-expanded donor iNKT cells ameliorate experimental aGVHD, 15,16 we tested the ability of ␣GC-expanded human CD4 ϩ and CD4 Ϫ iNKT-cell subsets to regulate the MLR, an in vitro correlate of the alloresponse. For this purpose, highly purified (supplemental Figure 4) normal donor CD4 ϩ and CD4 Ϫ NKT cells, autologous to responder T cells, were added to the allogeneic, HLA-mismatched MLR at an iNKT-to-responder (R) ratio of 10:1.…”

“…13 Remarkably, iNKT cells in G-CSF-mobilized grafts were shown to protect from experimental aGVHD while enhancing the GVL effect, 14 and in vitro-expanded donor iNKT cells alleviate aGVHD in a MHC haploidentical setting. 15,16 Recent work also found the ability of unmanipulated, adoptively transferred donor iNKT cells to protect from experimental aGVHD without prior in vitro expansion. 17 To directly test whether the protective role of donor iNKT cells shown in preclinical models also holds true in clinical allogeneic HSCT, we studied the effect of the dose of graft iNKT cells on the incidence and severity of aGVHD after a T cell-replete allogeneic HSCT from HLA-identical sibling donors.…”

Acute renal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation

“…Elevated IL-4 levels have been described in acute GvHD, 43,44 and the beneficial effect of natural killer cells on GvHD seems to be IL-4 dependent. [45][46][47][48] We found renal IL-4 expression to be significantly elevated in allogeneic LIP animals compared to syngeneic animals. Allogeneic HIP animals only showed a trend toward higher expression.…”

Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

“…Indeed, donor iNKTs expanded in vitro by stimulation with αGC attenuate GvHD. 90,91 Furthermore, in vivo injection of αGC or OCH (a homologue of αGC) attenuates GvHD severity via host iNKT production of IL-4 and Th2 polarization of donor T cells. 89 However, contradictory to these favorable observations, another study 92 reported that the administration of αGC (but not its N-acyl variant, C20:2) induces hyper-acute GvHD and rapid mortality in mice.…”