Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Faslpr or Fas ligandgld mutations develop significant numbers of B220+ CD4− CD8− double-negative (DN) αβ T cells (hereafter referred to as B220+ DN T cells) of poorly understood function. In this study, we show that B220+ DN T cells, whether generated in vitro or isolated from mutant mice, can suppress the ability of activated T cells to proliferate or produce IL-2, IL-10, and IFN-γ. B220+ DN T cells that were isolated from either lpr or gld mice were able to suppress proliferation of autologous and syngeneic CD4 T cells, showing that suppression is Fas independent. Furthermore, restoration of Fas/Fas ligand interaction did not enhance suppression. The mechanism of suppression involves inhibition of IL-2 production and its high affinity IL-2R α-chain (CD25). Suppression also requires cell/cell contact and TCR activation of B220+ DN T cells, but not soluble cytokines. These findings suggest that B220+ DN T cells may be involved in controlling autoreactive T cells in the absence of Fas-mediated peripheral tolerance.
HCT (79 pts) No HCT (38 pts) P-value logistic regression Unfavorable cytogenetics (n) 30 (37%) 7 (18%) 0.18 Secondary AML (n) 39 (49%) 15 (39%) 0.32 Early relapse (n) (>5% marrow blasts within 4.9 months of CR1 (range 0.9-10, median 3.75) 0 (0%) 13 (34%) <0.001 Twenty-four of the 38 (63%) non-HCT patients were HLA-typed and matched donors were found for 13 of these 24 patients (54%; 5 related, 8 unrelated). Seven of the 14 non-typed patients (50%) had financial barriers or refused HLA-typing. Only 2 of these 38 (5%) received HCT beyond CR1. Conclusion: These data suggest that HCT can be performed in CR1 in the majority of high-risk AML patients in whom it is currently recommended. Patients in whom HCT is not done are characterized by a poorer performance status (but not older age) and by early relapse. In the absence of these 2 factors, .75% of patients with high-risk AML under the age of 75 can receive HCT in CR1. A national study is planned to assess the extent to which these results can be generalized.
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