Role of the Passive Apoptotic Pathway in Graft-Versus-Host Disease

Abstract

Donor T cells have been shown to undergo apoptosis during graft-vs-host disease (GVHD). Although active apoptosis mediated through Fas/Fas ligand interactions has been implicated in GVHD, little is known about the role of the passive apoptotic pathway. To examine this question, we compared the ability of normal donor T cells and T cells overexpressing the antiapoptotic protein, Bcl-xL, to mediate alloreactive responses in vitro and lethal GVHD in vivo. In standard MLCs, T cells that overexpressed Bcl-xL had significantly higher proliferative responses but no difference in cytokine phenotype. Overexpression of Bcl-xL prolonged survival of both resting and alloactivated CD4+ and CD8+ T cells as assessed by quantitative flow cytometry, accounting for the higher proliferative responses. Analysis of engraftment in murine transplantation experiments demonstrated an increase in donor T cell chimerism in animals transplanted with Bcl-xL T cells, suggesting that overexpression of Bcl-xL prolonged T cell survival in vivo as well. Notably, transplantation of Bcl-xL T cells into nonirradiated F1 recipients also significantly exacerbated GVHD as assessed by mortality and pathological damage in the gastrointestinal tract. However, when mice were irradiated no difference in GVHD mortality was observed between animals transplanted with wild-type and Bcl-xL T cells. These data demonstrate that the passive apoptotic pathway plays a role in the homeostatic survival of transplanted donor T cells. Moreover, the susceptibility of donor T cells to undergo passive apoptosis is a significant factor in determining GVHD severity under noninflammatory but not inflammatory conditions.

Host Conditioning Is a Primary Determinant in Modulating the Effect of IL-7 on Murine Graft-versus-Host Disease

“…In that regard, we have previously shown that inhibition of T cell apoptosis alone can exacerbate GVHD lethality in nonirradiated recipients (37). In these studies, mice transplanted with donor T cells that were resistant to passive apoptotic cell death through overexpression of Bcl-x L had more severe GVHD.…”

Emergent autoimmunity in graft-versus-host disease

“…To obtain highly enriched populations of CD4 ϩ and CD8 ϩ T cells, splenic T-cell subpopulations were positively selected using the MACS magnetic cell separation system (Miltenyi Biotech, Auburn, CA), as previously described. 15 …”

Mouse models of graft-versus-host disease

“…Experimental data suggests that deletional tolerance by AICD is operative via the Fas (for CD4+) or TNFR (CD8 + ) pathways in Th1 cells and when there is a higher frequency of alloreactive cells (Combadiere et al, 1998;Min et al, 2004;Siegel et al, 2000;Zhang et al, 1997;Zheng et al, 1995). PCD or "death by neglect" is due to rapid downregulation of Bcl-2 and appears to be critical in non-irradiated, but not after irradiated BMT (Drobyski et al, 2002). Thus, distinct mechanisms of tolerance induced by apoptosis have a dominant role depending on the T cell subsets, the conditioning regimens and the histocompatibility differences.…”

“…Thus, distinct mechanisms of tolerance induced by apoptosis have a dominant role depending on the T cell subsets, the conditioning regimens and the histocompatibility differences. Nonetheless strategies aimed at selective elimination of donor T cells in vivo after HCT, either by targeting a suicide gene to the allo-T cells or by photodynamic cell purging appear promising in reducing experimental acute GVHD (Bondanza et al, 2006;Bonini et al, 1997;Bordignon et al, 1995;Drobyski and Gendelman, 2002).…”