| 1. |
- Jansson, Johan, et al.
(författare)
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Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects
- 2011
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 35:6, s. 800-807
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analysed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.
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| 2. |
- Mullen, Craig A, et al.
(författare)
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Evidence of B Cell Immune Responses to Acute Lymphoblastic Leukemia in Murine Allogeneic Hematopoietic Stem Cell Transplantation Recipients Treated with Donor Lymphocyte Infusion and/or Vaccination
- 2010
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:2, s. 226-238
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Tidskriftsartikel (refereegranskat)abstract
- These experiments explored mechanisms of control of acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation using a murine model of MHC-matched, minor histocompatibility antigen mismatched transplantation. The central hypothesis examined was that addition of active vaccination against leukemia cells would substantially increase the effectiveness of allogeneic donor lymphocyte infusion against ALL present in the host after transplant. While vaccination did increase the magnitude of type I T cell responses against leukemia cells associated with donor lymphocyte infusion, it did not lead to substantial improvement in long term survival. Analysis of immunological mechanisms of leukemia progression demonstrated that the failure of vaccination was not due to antigen loss in leukemia cells. However, analysis of survival provided surprising findings that, in addition to very modest type I T cell responses, a B cell response that produced antibodies that bind leukemia cells was found in long term survivors. The risk of death from leukemia was significantly lower in recipients that had higher levels of such antibodies. These studies raise the hypothesis that stimulation of B cell responses after transplant may provide a novel way to enhance allogeneic graft versus leukemia effects associated with transplantation.
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| 3. |
- Shand, Jessica C, et al.
(författare)
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Differential gene expression in acute lymphoblastic leukemia cells surviving allogeneic transplant.
- 2010
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 59:11, s. 1633-1644
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of allogeneic graft-versus-leukemia (GVL) activity in control of acute lymphoblastic leukemia is generally regarded as poor. One possible factor is dynamic adaptation of the leukemia cell to the allogeneic environment. This work tested the hypothesis that the pattern of gene expression in acute lymphoblastic leukemia cells in an allogeneic environment would differ from that in a non-allogeneic environment. Expression microarray studies were performed in murine B lineage acute lymphoblastic leukemia cells recovered from mice that had undergone allogeneic MHC-matched but minor histocompatibility antigen mismatched transplants. A limited number of genes were found to be differentially expressed in ALL cells surviving in the allogeneic environment. Functional analysis demonstrated that genes related to immune processes, antigen presentation, ubiquitination and GTPase function were significantly enriched. Several genes with known immune activities potentially relevant to leukemia survival (Ly6a/Sca-1, TRAIL and H2-T23) were examined in independent validation experiments. Increased expression in vivo in allogeneic hosts was observed, and could be mimicked in vitro with soluble supernatants of mixed lymphocyte reactions or interferon-gamma. The changes in gene expression were reversible when the leukemia cells were removed from the allogeneic environment. These findings suggest that acute lymphoblastic leukemia cells respond to cytokines present after allogeneic transplantation and that these changes may reduce the effectiveness of GVL activity.
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