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Available from: Jon van Rood, Jul 31, 2015
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    • "Minor alloantigens can also pose a barrier to transplantation despite their much lower allelic variation than MHC antigens. Historically, the first recognized minor histocompatibility antigens turned out to be encoded on the Y chromosome (Goulmy et al., 1976). In all, there are now nearly 20 known minor antigens in humans, with about equal genetic distribution between autosomes and the Y chromosome. "
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    ABSTRACT: The genetic disparity between the mother and fetus has long enticed immunologists to search for mechanisms of maternal tolerance to fetal antigens. The study of antigen-specific tolerance in murine and human pregnancy has gained new momentum in recent years through the focus on antigen-presenting cells, uterine lymphatics and fetal antigen-specific maternal T cell responses. In mice, we now know that these responses occur within the secondary lymphoid structures as they can be conveniently tracked through the use of defined, often transgenic fetal antigens and maternal T cell receptors. Although the secondary lymphoid organs are sites of both immunization and tolerization to antigens, the immunological processes that occur in response to fetal antigens during the healthy pregnancy must invariably lead to tolerance. The molecular properties of these maternal-fetal tolerogenic interactions are still being unraveled, and are likely to be greatly influenced by tissue-specific microenvironments and the hormonal milieu of pregnancy. In this article, we discuss the events leading to antigen-specific maternal tolerance, including the trafficking of fetal antigens to secondary lymphoid organs, the properties of the antigen-presenting cells that display them to maternal T lymphocytes, and the nature of the ensuing tolerogenic response. Experimental data generated from human biological specimens as well as murine transgenic models are considered.
    The International journal of developmental biology 10/2009; 54(2-3):421-30. DOI:10.1387/ijdb.082800et · 2.57 Impact Factor
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    • "Several MHag have been characterized in humans (Goulmy et al, 1976; Wang et al, 1995; Mutis et al, 1999; Brickner et al, 2001). The epitopes recognized in a GVL response may involve both shared host alloantigens, which can also induce GVHD, and unique tissue or tumour-specific antigens. "
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    ABSTRACT: Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.
    British Journal of Haematology 10/2009; 147(5):614-33. DOI:10.1111/j.1365-2141.2009.07886.x · 4.96 Impact Factor
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    ABSTRACT: Stem cell transplantation (SCT) is an accepted treatment for patients with hematological malignancies. Stem cell donor-derived T cells mediate both beneficial Graft-versus-Leukemia (GvL) effects and detrimental Graft-versus-Host Disease (GvHD). Relapse of the original disease can be treated with infusions of donor lymphocytes (DLI). Like SCT, DLI elicits both GvHD and GvL. The risk of severe GvHD is especially high if the stem cell donor and patient are not fully matched for human leukocyte antigens (HLA). To minimize GvHD after HLA-mismatched SCT DLI should consist of pre-selected donor T cells that display reactivity restricted to the patient's residual leukemic or hematopoietic cells. This thesis focuses on exploring the alloHLA-A2 T cell repertoire and testing the feasibility of generating alloHLA-A2-restricted T cells specific for the hematopoietic system-restricted minor Histocompatibility antigens (mHags) HA-1 or HA-2. We describe several new methods of alloHLA-restricted antigen-specific T cell stimulation. However, we also show that alloHLA-recognition by T cells is inherently crossreactive. Unfortunately, currently available technologies can not readily distinguish between crossreactive and antigen-specific alloHLA-restricted T cells. We therefore conclude that generation of alloHLA-restricted antigen-specific T cells is as yet not feasibible in a clinical setting.
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