Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT

Abstract

Utilizing a clinically relevant haploidentical (HI) murine transplant model, lethally irradiated B6D2F1 (H2K b/d ) mice were transplanted with T cell-depleted (TCD) BM from B6CBAF1 (H2K b/k ) mice. We found that administration of IL-15 significantly increases the numbers of CD8 þ T and natural killer (NK) cells in spleen and BM after transplantion without GVHD. Graft-versus-tumor (GVT) potency of the graft was evaluated upon tumor challenge using P815 tumor cells (H2 d ). IL-15 administration without T-cell infusion did not result in any survival improvement. However, IL-15 in combination with very low-dose T-cell infusion (1 Â 10 4 ) significantly increased GVT activity and improved survival in recipients of HI hematopoietic SCT (HSCT). This effect was observed when IL-15 was given at a later time point, rather than immediately following transplantation. IL-15 administration also specifically increased slow-proliferative CD8 þ T-cell proliferation and IFN-g secretion in CD8 þ T cells in recipients of CFSE (carboxyfluorescein succinimidyl ester)-labeled HI T-cell infusion, whereas there was no effect on CD4 þ T-cell proliferation, suggesting the critical effect of IL-15 on CD8 þ T-cell homeostasis in HI host. We conclude that IL-15 can be used for enhancing antileukemia effect of HI-HSCT, which requires presence of donor-derived T cells.

Immune Reconstitution after Haploidentical Hematopoietic Stem Cell Transplantation

“…Using a clinically relevant haploidentical murine transplantation model, Sauter et al [58] found that IL-15 administration significantly increased CD8 þ T cell and NK cell reconstitution and also improved graft-versus-leukemia/graft-versus-tumor activity in recipients of haploidentical HSCT. These authors also demonstrated that IL-15 increased intracellular IFN secretion in undivided and slowly proliferating CD8 þ T cells in recipients of carboxyfluoresceinsuccinimidyl esterelabeled T cells, with no change in the IFN-secreting alloreactive/rapidly proliferative cell population [58].…”

“…Unfortunately, serious infections and disease relapse resulting from delayed immune reconstitution remain the 2 most frequent causes of mortality after allogeneic HSCT, particularly in patients who received extensively TCD CD34 þ cell megadose allografts [10][11][12][13][14][15]. Advances in the understanding of immune recovery profiles in haploidentical recipients [8,, along with new methods of modifying donor T cells [48][49][50] and natural killer (NK) cells [51], have made it possible to establish new strategies to improve post-transplantation immunologic reconstitution [9,[52][53][54][55][56][57][58].…”

Allogeneic Splenocyte Transfer and Lipopolysaccharide Inhalations Induce Differential T Cell Expansion and Lung Injury: A Novel Model of Pulmonary Graft-versus-Host Disease

“…The IL-15 upregulation seen in AlloLPS mice is likely an important pro-CD8 T cell stimulus. Indeed, IL-15 has been shown to cause formation of memory CD8 T cells, CD8 T cell proliferation, and CD8 IFN-γ production post HCT [21], [22]. CD8 T cells have previously been implicated in systemic GVHD pathophysiology [23], [24].…”

Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation

“…IL15 has been shown to significantly increase the reconstitution of CD8+ T cells and NK cells and improve the GvL effect in haploidentical murine models [125]. Sauter et al [126] reported better lymphocyte reconstitution after IL-15 administration in T-cell depleted allogeneic HSCT; however, it has been shown to worsen GvHD.…”