Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor Activity

Abstract

Graft-versus-host disease (GVHD) can be prevented by Fas-mediated selective depletion of host-sensitized donor lymphocytes ex vivo. We tested the hypothesis that Fas-mediated depletion of lymphocytes in the absence of host-specific antigenic stimulation can alleviate GVHD. Brief exposure (24 hours) of unstimulated donor lymphocytes to Fas ligand (FasL) ex vivo results in balanced apoptosis of CD8(+) and CD4(+) subsets with preferential depletion of CD62L and CD69, increased T regulatory fractions, and sustained responses to stimulation. This procedure ameliorates weight loss and improves the clinical and histologic score of skin and gastrointestinal GVHD with and without concurrent transplantation of hematopoietic progenitors and irrespective of conditioning-induced tissue injury. Although FasL-resistant donor T cells are less potent effectors of GVHD, they facilitate hematopoietic progenitor engraftment when infused with or after the graft and retain the potential to elaborate graft-versus-tumor reactions. These findings in a preclinical model together with the known trophic effects of FasL on primitive hematopoietic progenitors suggest that brief ex vivo incubation of hematopoietic grafts with FasL may improve the outcome and safety of clinical T cell-replete allogeneic and haploidentical transplants.

Apoptotic signaling through Fas and TNF receptors ameliorates GVHD in mobilized peripheral blood grafts

“…[8][9][10][11] We have recently reported that selective sensitization to host Ags is dispensable, and a short apoptotic challenge ex vivo is equally effective in reducing GvH effector propensity in murine hematopoietic cell grafts. 14 Importantly, both approaches of Fas-mediated deletion of host-primed and unsensitized donor T cells preserved antiviral and graft versus tumor (GVT) activities. 10,11,14 Apoptosis-based functional deletion of T cells might prove itself an effective approach to GVHD prophylaxis because murine and human hematopoietic progenitors are largely insensitive to apoptotic signaling through the TNF family receptors.…”

“…14 Importantly, both approaches of Fas-mediated deletion of host-primed and unsensitized donor T cells preserved antiviral and graft versus tumor (GVT) activities. 10,11,14 Apoptosis-based functional deletion of T cells might prove itself an effective approach to GVHD prophylaxis because murine and human hematopoietic progenitors are largely insensitive to apoptotic signaling through the TNF family receptors. [15][16][17][18][19] On the contrary, the dual activity of TNF family receptors includes trophic signaling in murine and human progenitors and apoptotic signaling in the differentiated progeny, which acquires sensitivity to AICD during maturation and activation.…”

Negative selection by apoptosis enriches progenitors in naïve and expanded human umbilical cord blood grafts

“…Although GvH reactivity is undetected in UCB xenochimeras and the severity of GvHD is generally reduced in human UCB transplants, it sometimes imposes severe morbidity. [7][8][9][10]16 We have recently demonstrated that exposure of donor inoculum to an apoptotic challenge in the absence of host-specific sensitization reduces GvHD severity in mice grafted with haploidentical T cells 26 and human mobilized-peripheral blood xenografts. 27 In view of the preserved-engraftment facilitating and graft versus tumor activities of T cells pretreated with death ligands, it remains to be determined whether UCB T cells have reduced-GvH reactivity following functional depletion.…”

“…17,18 Insensitivity of hematopoietic progenitors to apoptosis can be used to improve the outcome of transplants, conferring immune privilege to the graft 24,25 and fostering progenitor activity. [19][20][21][22] A pretransplant apoptotic challenge with Fas-ligand (FasL) and TNF-α reduces significantly the incidence and severity of GvHD in haploidentical-and xenogeneic-murine transplants, 26,27 and improves early myeloid reconstitution. 20,22 In this study we assessed possible implementation of apoptotic signaling in several aspects of UCB cell transplantation.…”

Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD

“…However, GvL is not enhanced by this approach. 10 More recently, CD19-specific chimeric antigen receptor donor-derived allogeneic T-cells were given post allogeneic BMT. None of the 10 patients developed GvHD after receiving chimeric antigen receptor-modified donor T-cells.…”