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  • Immunotherapy  (2)
  • 60H15  (1)
  • CTL  (1)
  • Springer  (4)
  • 1
    ISSN: 1432-0851
    Keywords: Draining lymph nodes ; T cells ; Gene modification ; Immunotherapy ; Interferon γ
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Gene modification of tumor cells with the cDNA for interferon γ (IFNγ) has been shown to increase the immunogenicity of some tumor cells. In order to explore further the possible therapeutic relevance of these previous findings, two clones of the nonimmunogenic MCA-102 fibrosarcoma of C57BL/6 origin were retrovirally transduced with the cDNA encoding murine IFNγ: 102.4JK (4JK), a clone with relatively high major histocompatibility complex (MHC) class I expression, and 102.24JK (24JK), a clone with low expression of surface MHC class I molecules. Retroviral transduction of tumor cells with the cDNA encoding for IFNγ resulted in a substantial up-regulation of MHC class I surface expression in the 24JK clone but little change of class I in the 4JK clone. In an attempt to generate antitumor lymphocytes, these gene-modified cells were inoculated into mouse footpads and draining lymph nodes (DLN) were removed, dispersed, and cultured in vitro for 10 days with irradiated tumor cells and interleukin-2. DLN from mice bearing either unmodified tumor or tumor transduced with cDNA encoding neomycin resistance (Neo R) or IFNγ, were used to treat recipients harboring 3-day pulmonary metastases induced by the parental, unmodified tumor. Treatment with DLN cells obtained following the injection of 24JK tumor cells modified with the gene for IFNγ significantly reduced the number of pulmonary metastases in four separate experiments, compared to groups treated by DLN cells generated from inoculation of either the unmodified, parental 24JK clone or the same clone transduced with theNeo R gene only. In contrast, DLN cells induced either by IFNγ-transduced 4JK (high expression of MHC class I) or an unmodified 4JK tumor (moderate expression of MHC class I) had significant but equal therapeutic efficacy. Although the in vitro growth rate of tumor cell lines was unaffected by the insertion of the mouse IFNγ cDNA, their in vivo (s.c.) growth rates were significantly slower than those of the nontransduced tumors. Thus, after retroviral transduction of the murine IFNγ cDNA into a nonimmunogenic tumor with a very low level of surface expression of MHC class I, modified tumor cells could elicit therapeutic T cells from DLN capable of successfully treating established pulmonary metastases upon adoptive transfer. This strategy significantly confirms previous observations on the potential therapeutic effects of gene modification of tumor cells with IFNγ and extends the realm of therapeutic possibilities to include the use of DLN cells for the development of T-cell based immunotherapies against nonimmunogenic human tumors.
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  • 2
    ISSN: 1432-0851
    Keywords: Melanoma ; MAGE-1 ; Tumor-infiltrating lymphocytes ; Immunotherapy ; Peptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The MAGE-1 gene encodes a tumor-specific antigen, MZ2-E, which is recognized by cloned, specific cytolytic T cells (CTL) derived from the peripheral blood of a patient with melanoma. We have produced a MAGE-1-specific CTL line derived from the tumor-infiltrating lymphocytes (TIL) of a melanoma patient by weekly restimulation with autologous EBV-B cells pulsed with the synthetic HLA-A1-restricted MAGE-1 epitope nonapeptide EADPTGHSY. The 1277. A TIL line grew in long-term culture in low-dose interleukin-2 (IL-2) and IL-4, and exhibited antigen-specific, MHC-class-I-restricted lysis of HLA-A1-bearing MAGE-1+ cell lines. Cytolysis of target cells pulsed with the synthetic MAGE-1 decapeptide KEADPTGHSY was superior to that of cells pulsed with the immunodominant nonapeptide. Single amino-acid or even side-chain substitutions in the immunodominant nonamer abrogated cytolysis. 1277. A TIL specifically secreted tumor necrosis factor α after co-incubation with HLA-A1-expressing MAGE-1+ cell lines or fresh tumor. These data suggest that tumor-antigen-specific, MHC-restricted CTL may be grown from TIL in the presence of synthetic epitope peptides and expanded for adoptive immunotherapy in melanoma patients.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1534-4681
    Keywords: Melanoma ; Dendritic cells ; Melanoma-associated antigens ; MART-1 ; Recombinant viral vectors ; Poxviruses ; CTL
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Dendritic cells (DC) are potent professional antigen-presenting cells that can activate naive T lymphocytes and initiate cellular immune responses. As adjuvants, DC may be useful for enhancing immunogenicity and mediating tumor regression. Endogenous expression of antigen by DC could offer the potential advantage of allowing prolonged constitutive presentation of endogenously processed epitopes and exploitation of multiple restriction elements for the presentation of the same antigen. Methods: DC were prepared from the peripheral blood of HLA A*0201 patients with metastatic melanoma in the presence of IL-4 (1000 IU/mL) and GMCSF (1000 IU/mL). Recombinant vaccinia and fowlpox viruses encoding the hMART-1 gene were constructed and used to infect DC. The efficiency of infection and expression of the MART-1 antigen were assessed by immunohistochemistry and intracellular FACS analyses. Cytotoxic lymphocytes (CTL) were generated by the stimulation of CD8+ T cells, with DC expressing the recombinant gene. Reactivity of the CTL was determined at weeks 1 and 2 by the amount of IFN-γ released. Results: DC were infected with recombinant poxviruses and demonstrated specific melanoma antigen expression by immunohistochemistry, immunofluorescence, and intracellular FACS analysis. The expression by DC of MART-1 MAA after viral infection was sufficient to generate CD8+ T lymphocytes that recognized naturally processed epitopes on tumor cells in 10 of 11 patients. Conclusions: Human DC are receptive to infection by recombinant poxviruses encoding MAA genes and are capable of efficiently processing and presenting these MAA to cytotoxic T cells. The potential advantage of this approach is the ability to present specific antigen independent of the identification of the epitope or the MHC restriction element. This strategy may be useful for the identification of relevant epitopes for a diverse number of HLA alleles and for active immunization in patients.
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  • 4
    ISSN: 1572-9036
    Keywords: 58G11 ; 58G32 ; 60H15 ; Bochner's theorem ; Brownian motion and heat flow ; spectrum of the Laplacian ; hyperbolic manifolds ; cohomology with compact support
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Bochner's theorem that a compact Riemannian manifold with positive Ricci curvature has vanishing first cohomology group has various extensions to complete noncompact manifolds with Ricci possibly negative. One still has a vanishing theorem for L 2 harmonic one-forms if the infimum of the spectrum of the Laplacian on functions is greater than minus the infimum of the Ricci curvature. This result and its analogues for p-forms yield vanishing results for certain infinite volume hyperbolic manifolds. This spectral condition also imposes topological restrictions on the ends of the manifold. More refined results are obtained by taking a certain Brownian motion average of the Ricci curvature; if this average is positive, one has a vanishing theorem for the first cohomology group with compact supports on the universal cover of a compact manifold. There are corresponding results for L 2 harmonic spinors on spin manifolds.
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