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- Tötterman, Thomas H., et al.
(author)
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Targeted superantigens for immunotherapy of haematopoietic tumours
- 1998
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In: Vox Sanguinis. - 0042-9007 .- 1423-0410. ; 74:Supp 2, s. 483-487
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Journal article (peer-reviewed)abstract
- With the exception of childhood common acute lymphoblastic leukaemia (cALL), treatment of other hematopoietic B cell lineage tumours such as non-Hodgkin's lymphoma (B-NHL), adult ALL and multiple myeloma (MM) is unsatisfactory. Similarly, the therapeutic outcome of acute and chronic myeloid leukaemia (AML, CML) is frequently dismal. At the same time, leukaemia/lymphoma cells represent ideal targets for immunotherapy. The present review summarizes our preclinical experience with a novel type of cytotoxic T cell based immunotherapy for B-lineage and myeloid tumours. Staphylococcal enterotoxin-derived superantigens (SAgs) are among the most potent T cell activators known, linking the T cell receptor to HLA-DR on natural target cells. SAgs were genetically engineered to reduce DR binding and were then fused to Fab parts of tumour-directed monoclonal antibodies (mAbs). Using these "targeted" SAgs, highly efficient lysis of B-lineage (B-NHL, B-CLL, ALL, MM) and myeloid (AML, CML) tumour cells by T-cells was achieved in vitro and in an animal model. We are entering an interesting era of innovative cancer therapy based on novel man-made biotherapeutic agents.
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| 4. |
- Belfrage, Hans, et al.
(author)
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Combined activation of murine lymphocytes with staphylococcal enterotoxin and interleukin-2 results in additive cytotoxic activity
- 1994
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In: Cancer Immunology and Immunotherapy. - 1432-0851. ; 38:4, s. 71-265
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Journal article (peer-reviewed)abstract
- This report demonstrates that in vitro activation of murine spleen cells with interleukin-2 (IL-2) or the bacterial superantigen staphylococcal enterotoxin A (SEA) results in different patterns of activation and function of cytotoxic cells. Lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity (ADCC) are mainly mediated by IL-2 activated natural killer (NK) cells. SEA is the most powerful T cell mitogen known so far and retargets cytotoxic T lymphocytes (CTL) to tumors expressing major histocompatibility complex (MHC) class II in staphylococcal-enterotoxin-dependent cellular cytotoxicity (SDCC). Culture of mouse spleen cells with SEA led to expansion and activation of T cells, which demonstrated strong SDCC activity and some NK-like cytotoxicity after 5 days in culture. Cell sorting revealed that both CD8+ and CD4+ T cells mediated SDCC but the former were more effective. Phenotypic analysis showed that SEA preferentially stimulated and expanded T cells expressing T cell receptor V beta 11, in particular CD8+ T cells. Combined activation with SEA and IL-2 resulted in simultaneous induction of T and NK cell cytotoxicity. Moreover, IL-2 had additive effects on SEA-induced SDCC. Combined treatment with SEA and IL-2 might therefore be an approach to induce maximal cytotoxicity against tumors and to recruit both T and NK cells in tumor therapy.
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| 5. |
- Belfrage, Hans, et al.
(author)
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Enhanced and prolonged efficacy of superantigen-induced cytotoxic T lymphocyte activity by interleukin-2 in vivo
- 1995
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In: Cancer Immunology and Immunotherapy. - 1432-0851. ; 41:2, s. 87-94
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Journal article (peer-reviewed)abstract
- The bacterial superantigen, staphylococcal enterotoxin A (SEA) activates T cells with high frequency and directs them to lyse MHC-class-II-expressing cells in superantigen-dependent cell-mediated cytotoxicity (SDCC). Treatment of mice with SEA induced strong CD8+ T-cell(CTL)-mediated SDCC, as well as abundant cytokine production from CD4+ and CD8+ T cells. However, both cytotoxicity and cytokine release were transient. In contrast, combined treatment with SEA and recombinant interleukin-2 (rIL-2) increased peak levels and maintained CTL activity. These effects were concomitant with an increased number of SEA-reactive V beta 11+ T cells. Both the CD4+ and CD8+ populations contained higher frequencies of cells expressing IL-2 receptor (IL-2R) alpha beta, which suggests that continuous IL-2R signaling preserves its high expression and subsequently prevents loss of growth factor signals necessary for expansion of T cells. Although IL-2R expression was increased among both CD4+ and CD8+ cells, only the cytotoxic function of CTL, but not cytokine production from either CD4 or CD8, was augmented. These findings demonstrate that treatment with rIL-2 potentiates superantigen-induced cytotoxicity and maintains high CTL activity. rIL-2 might therefore be useful in improving superantigen-based tumor therapy.
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| 6. |
- Belfrage, Hans, et al.
(author)
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Prevention of superantigen induced down-regulation of T cell mediated cytotoxic activity by IL-2 in vivo. 1996 Accepted for publication in Immunology
- 1997
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In: Immunology. - 0019-2805. ; 90:2, s. 8-183
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Journal article (peer-reviewed)abstract
- Administration of staphylococcal enterotoxin A (SEA) to mice induces profound activation, cytokine production and cytotoxic activity of both CD4+ and CD8+ T cells, but subsequently activated cells are deleted or become anergic. This study demonstrates that administration of interleukin-2 (IL-2) can prevent sea-induced hyporesponsiveness in CD8+ cytotoxic T lymphocytes (CTL). Repeated injections with sea every fourth day resulted in severely reduced cytotoxic activity in the spleen, which correlated with a reduced number of sea-responsive T-cell receptor (TCR)-V beta 11+ CD8+ cells. Studies of purified TCR-V beta 11+ CD8+ cells showed that they possessed intact cytotoxic activity per cell compared with cells from mice given a single injection of SEA, indicating that deletion was the main mechanism for the reduced cytotoxic activity. Combined treatment with SEA and IL-2 increased the number of cytotoxic cells in the spleen after each SEA injection and prevented the down-regulation of cytotoxic activity. Increased cytotoxic activity could be related to increased number and proliferation of CD8+ IL-2R alpha + cells, suggesting that administration of IL-2 maintained IL-2 responsiveness among CD8+ cells. Studies of sorted TCR-V beta 11+ CD8+ cells demonstrated that combined treatment with SEA and IL-2 also increased cytotoxic activity per cell compared with treatment with SEA alone. Taken together, IL-2 administration in vivo augmented SEA-induced expansion of T cells as well as the cytotoxic activity per CTL, and prevented SEA-induced cell deletion.
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| 7. |
- Belfrage, Hans, et al.
(author)
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Prevention of superantigen-induced tolerance in vivo by interleukin-2 treatment. 1996 Submitted
- 1997
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In: Cancer Immunology and Immunotherapy. - 1432-0851. ; 44:2, s. 77-82
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Journal article (peer-reviewed)abstract
- Injection of the superantigen staphylococcal enterotoxin A (SEA) activates both CD4+ and CD8+ T cells expressing certain families of T cell receptor (TCR) variable-region beta (V beta) chain. T cells respond with profound cytokine production and induction of cytotoxicity. Repeated injections, however, cause deletion and anergy of both CD4+ and CD8+ T cells, resulting in reduced frequency of SEA-responsive cells TCR-V beta11+ as well as reduced cytokine levels in serum upon challenge with SEA. Exogenous interleukin-2 (IL-2) in vivo rescued SEA-responsive CD4+ and CD8+ cells from SEA-induced deletion and/or increase expansion of SEA-primed cells as well as preventing downregulation of endogenous IL-2 production in vivo. Combined treatment with SEA and IL-2 also superinduced production of important cytokines for the cytotoxic function of T cells, tumour necrosis factor alpha, interferon gamma and IL-6, on a cellular level. These studies show that continuous stimulation with IL-2 in vivo could be useful for superantigen-based immunotherapy by induction of excessive T cell activation and by prevention of the development of T cell deletion and anergy.
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| 9. |
- Dohlsten, John, 1981, et al.
(author)
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Sustainable elite sport: Swedish athletes' voices of sustainability in athletics
- 2021
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In: Qualitative Research in Sport Exercise and Health. - : Informa UK Limited. - 2159-676X .- 2159-6778. ; 13:5, s. 727-742
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Journal article (peer-reviewed)abstract
- Elite sport is a precarious context and as athletes are pushing their physical and mental boundaries to enhance performance, consequences can be devastating. In contrast to arguments that elite sport cannot be sustainable, some scholars have argued that with certain considerations and precautions, elite sport can have fewer unsustainable consequences. However, the current literature has missed to capture athletes' voices regarding sustainability in elite sport. Therefore, this article aims to give voice to athletes and their needs and concerns regarding sustainable elite sport and through this, to extend the existing elite sport sustainability conceptualisation with knowledge from the athlete perspective. Focus-group interviews were conducted with 15 high performance athletes. The findings suggest that athletes need athlete-centred coaching, focus on holistic perspectives, and co-creation of their overall development. However, athletes also seem to adapt and accept commodity structures, as their focus on results overrules most aspects regarding long-term health and well-being.
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| 10. |
- Dohlsten, M, et al.
(author)
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Lymphocyte subpopulations and lymphokine production in children with constitutional aplastic anemia
- 1988
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In: Pediatric Hematology & Oncology. - : Informa UK Limited. - 1521-0669 .- 0888-0018. ; 5:2, s. 143-151
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Journal article (peer-reviewed)abstract
- The expression of lymphocyte surface markers as well as the production of interleukin-2 (IL-2) and interferon-gamma (IFN) by mitogen-stimulated peripheral blood mononuclear cells (MNC) have been studied in five children with constitutional aplastic anemia. A significantly reduced T4/T8 ratio was found and two of five patients also had a reduced percentage of B cells. One patient had a high percentage of HLA-DR positive T8+ cells, very suggestive of a high degree of circulating activated T suppressor/cytotoxic cells. IL-2 production was reduced in two patients, whereas IFN production was only reduced in one of these. The abnormalities found correlate with the duration of the bone marrow failure. The patients with the longest duration of bone marrow failure also exhibited the lowest T4/T8 ratio. No spontaneous IFN production was detected in any of the patients. There was no clinical benefit or reversal of the immune abnormalities during and following treatment with cimetidine and cyclosporine A in two patients.
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