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Immune response during tumor therapy with antibody-superantigen fusion proteins.

Abstract
To engineer superantigens (SAg) to express tumor reactivity, we genetically fused the Fab-part of the tumor-reactive MAb C215 and the bacterial SAg staphylococcal enterotoxin A (SEA). Treatment of mice carrying established lung micrometastases of the C215-transfected syngeneic B16 melanoma with 3-4 daily injections of C215Fab-SEA resulted in strong antitumor effects, while only moderate effects were seen when treatment was given every 4th day (intermittent treatment). High serum levels of IL-2, TNF-alpha, IFN-gamma and strong induction of CTLs (cytotoxic T lymphocytes) were noted after priming with the fusion protein. T cells responded well to 3 daily injections of C215Fab-SEA and then gradually entered a hyporesponsive state, characterized by a reduced ability to produce IL-2, TNF-alpha and IFN-gamma and failure to mediate cytotoxicity in vitro. Intermittent treatment was characterized by increased levels of IL-10, concomitant with accentuated loss of IL-2, TNF-alpha and IFN-gamma production. A 10-fold increase in SEA-reactive TCR V(beta)3+ CD4+ cells was observed in the spleen, while a loss of TCR V(beta)3+ CD8+ and V(beta)11+ CD8+ cells was noted. This is in striking contrast to injections of native SEA which induced a marked deletion of TCR V(beta)3+ CD4+ T cells, but not of CD8+ cells. Recovery of the TH1 cytokine profile occurred within 1-2 weeks, while restoration of cytotoxicity required several months and correlated with recovery of TCR V(beta)3+ CD8+ and TCR V(beta)11+ CD8+ T cells. These results show that the temporal relationship of SAg stimulations dictates the cytokine profile. Moreover, different mechanisms appear to regulate hyporesponsiveness in CD4+ and CD8+ T cells.
AuthorsA Rosendahl, J Hansson, A Sundstedt, T Kalland, M Dohlsten
JournalInternational journal of cancer (Int J Cancer) Vol. 68 Issue 1 Pg. 109-13 (Sep 27 1996) ISSN: 0020-7136 [Print] United States
PMID8895549 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Enterotoxins
  • Immunoglobulin Fab Fragments
  • Recombinant Fusion Proteins
  • Superantigens
  • enterotoxin A, Staphylococcal
Topics
  • Animals
  • Antibodies, Monoclonal (genetics)
  • Antigens, Neoplasm (immunology)
  • Enterotoxins (immunology, therapeutic use)
  • Female
  • Humans
  • Immunoglobulin Fab Fragments (immunology, therapeutic use)
  • Immunotherapy
  • Lymphocyte Activation
  • Lymphoma, B-Cell
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental (immunology, therapy)
  • Recombinant Fusion Proteins (immunology)
  • Superantigens (immunology, therapeutic use)
  • T-Lymphocytes (immunology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • Transfection
  • Tumor Cells, Cultured

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