Abstract Compelling evidences indicate a key role for regulatory T cells (Treg) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of Tregs. We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402–restricted manner. Importantly, they recognized HLA-DRB1*04–matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4+CD25+Foxp3+GITR+CD127− Treg phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of Tregs strongly inhibited the expansion of natural killer (NK), NK T, and CD8+ T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8+ T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201–restricted peptide in the presence of Tregs strongly inhibited the induction of anti–WT1-126 CD8+ CTL responses as evidenced by both very low cytotoxic activity and IFN-γ production. Moreover, these Treg clones specifically produced granzyme B and selectively induced apoptosis in WT1-84–pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti–WT1-84 interleukin-5+/granzyme B+/Foxp3+ CD4+ Tregs in five of eight HLA-DR4+ acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of Tregs in cancer patients. [Cancer Res 2008;68(15):6350–9]
Infertility is a major late effect of hematopoietic stem cell transplants (HSCT). In this study, we attempted to evaluate incidence of fertility recovery (FR) in patients with aplastic anemia (AA) as well the impact of patient's characteristics and transplantation procedures following allogeneic HSCT.
The recommended therapy for severe aplastic anemia (SAA) in younger patients with a matched sibling donor (MSD) is allogeneic hematopoietic cell transplantation (allo-HCT). A number of conditioning regimens and protocols have been used for these patients. Here we report a homogeneous cohort of SAA patients receiving a uniform transplantation protocol. This study is a retrospective analysis of 82 consecutive patients with SAA who underwent MSD allo-HCT at a single center. The median duration of follow-up for survivors was 100 months, the 10-year overall survival (OS) was 87.5%, and the 10-year event-free survival was 75.3%. The OS was 97.4% for "mobilized" bone marrow (BM) graft recipients and 78.9% for "nonmobilized" BM graft recipients (P = .01. The cumulative incidence of acute graft-versus-host disease (GVHD) was 25.6%, that of chronic GVHD was 27.16%, and that of graft failure was 16.2%. Recipient age ≥30 years and transplantation at >6 months after SAA diagnosis were associated with a increased risk of events. In the presence of a fully matched sibling donor, allo-HCT with a mobilized BM graft and fludarabine-cyclophosphamide conditioning is an efficacious and safe approach. Early transplantation is associated with a better outcome, emphasizing the importance of not delaying transplantation in these patients. Prospective trials are needed to determine the optimal regimen.
