Vaccines in leukemia.
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Antigens, Neoplasm↗
Biomedical subjects
Eric Wieder
Publications and source records attributed to Eric Wieder.
Effects of IL-7 on early human thymocyte progenitor cells in vitro and in SCID-hu Thy/Liv mice.
IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34(+) subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34(high)CD5(+)CD1a(-) thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4(+)CD8(+) thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4(+)CD3(+)CD8(-) and CD8(+)CD3(+)CD4(-) thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.
Animals↗
Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells.
We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2-restricted nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or allogeneic bone marrow transplant. Some patients with persistent disease also have circulating PR1-specific T cells, however, suggesting the likelihood of immune tolerance. Here we show that both high- and low-avidity PR1-specific T cells from the peripheral blood of healthy donors can be identified and selectively expanded in vitro. Although high-avidity PR1-specific T cells killed CML more effectively than low-avidity T cells, only high-avidity T cells underwent apoptosis when stimulated with high PR1 peptide concentration or when exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific T cells could be identified or expanded from newly diagnosed leukemia patients, whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1-specific T cells were identified in IFN-sensitive patients in cytogenetic remission, however. These results provide evidence that CML shapes the host immune response and that leukemia outgrowth may result in part from leukemia-induced selective deletion of high-avidity PR1-specific T cells.
Apoptosis↗
Overexpressed differentiation antigens as targets of graft-versus-leukemia reactions.
The graft-versus-leukemia (GVL) effect associated with allogeneic blood and marrow transplantation has largely been a clinically described phenomenon until recently. We are beginning to understand the cellular and molecular nature of GVL, and in this review the authors highlight the potential for self-antigen-specific T lymphocytes to contribute to GVL. The authors focus on myeloid tissue-restricted proteins as GVL target antigens in CML and AML, and in particular on proteinase 3 and other azurophil granule proteins as targets for both autologous and allogeneic T-cell responses. Finally, the authors discuss myeloid self-antigen-directed alloreactivity in the context of our evolving understanding of the critical molecular determinants of allogeneic T-cell recognition. By altering T-cell receptor affinity, peptide specificity can be maintained and the potency of immunity can be enhanced in the MHC-mismatched setting.
Antigens, Differentiation↗