A Phase I Trial with a Hybrid Cell Vaccine in Patients with Metastatic Melanoma
Uwe TrefzerGuido WeingartY. ChenKarin AdrianHeike AudringH. WinterYugang GuoWolfram SterryPeter Walden
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T-lymphocytes, unlike B lymphocytes, predominantly recognize antigen when it is associated with membrane-bound products of the major histocompatibility complex (MHC).1 2 3 This "dual" recognition (i.e., for both antigen and the MHC) is important for activation of both cytotoxic effector T cells and immunoregulatory T cells. Cytotoxic T cells lyse specific target cells, including tumor cells and cells infected with virus, whereas immunoregulatory T cells act as inducers or suppressors for interactions among T cells, B cells, macrophages, and other cells.The exquisite specificity of T cells has long been thought to be determined by unique, clonally distributed (clonotypic) cell-surface receptors. Because . . .
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T lymphocytes, unlike B lymphocytes, predominantly recognize antigen when it is associated with membrane-bound products of the major histocompatibility complex (MHC)(l–4). This "dual" recognition is important for activation of both cytotoxic effector T cells and immunoregulatory T cells. T cells act as inducers or suppressors for interactions between T cells, B cells, macrophages and other cells (8–13).
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Activation of T cells is normally promoted by interaction of T cell receptors with complexes of antigenic peptide bound to MHC (major histocompatibility complex) proteins on the surface of antigen-presenting cells (APCs). However, Ge et al. report that activation of naïve or CD8+ T cells can occur with exposure to soluble peptide-MHC complexes in the absence of APCs. Their results indicated that activation actually occurred through transfer of peptides to MHC molecules expressed by the T cells. Thus, T cells were only activated if they expressed the same MHC as the one with which they were stimulated. Furthermore T cells that had been exposed to MHC-peptide monomers and then washed could subsequently activate naïve T cells, apparently by presenting the peptide antigen on their cell surface as would a professional APC. Given that soluble peptide-MHC complexes are likely to exist in serum or synovial fluid, the authors propose that such presentation of antigen by T cells in vivo could influence T cell maturation.Q. Ge, J. D. Stone, M. T. Thompson, J. R. Cochran, M. Rushe, H. N. Eisen, J. Chen, L. J. Stern, Soluble peptide-MHC monomers cause activation of CD8+ T cells through transfer of the peptide to T cell MHC molecules. Proc. Natl. Acad. Sci. U.S.A. 99, 13729-13734 (2002). [Abstract] [Full Text]
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The interaction of nominal Ag with major histocompatibility complex (MHC)-restricted T cells and accessory cells was studied by analyzing the effect of structurally related antigens on the response of antigen-specific MHC-restricted T cell hybridomas. The copolymer L-glutamic acid50-L-tyrosine50 (GT) completely inhibits the response of L-glutamic acid60-L-alanine40-L-tyrosine10 (GAT)-specific, I-Ad-restricted T cell hybridomas to GAT plus accessory cells. This inhibition is specific, as hybridomas of other specificities are not inhibited under identical conditions, and is unique to the GT antigen, as other similar copolymers are not inhibitory. The inhibitory effect is reversible by adding increasing amounts of GAT. Antigen-pulsing experiments localized the inhibition to the level of antigen-presenting cell (APC). GT-prepulsed APC are not inhibitory in cell-mixing experiments and can present other antigens. GT only inhibits the nominal antigen-directed component of a GAT-specific, autoreactive hybrid's response. Together these findings suggest that GT causes inhibition by competing for GAT association at the accessory cell. GT interferes with GAT presentation by an I-Adxb F1 APC to a BALB/c, I-Ad-restricted, but not B10, I-Ab-restricted, T cell hybridoma, and GT inhibits presentation by GAT-prepulsed APC. The implications of these findings for MHC-restricted presentation of antigen are discussed.
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Cytotoxic T lymphocytes (CTLs) recognize major histocompatibility complex (MHC) class I molecules, normally composed of a heavy chain, a beta 2-microglobulin (beta 2m), and peptide antigens. beta 2m is considered essential for the assembly and intracellular transport of MHC class I molecules as well as their peptide presentation to CTLs. Contrary to this dogma, we now report the generation of allospecific and restricted CD8+ and TCR alpha beta+ CTLs (where TCR is T-cell receptor) capable of killing beta 2m-deficient cells. Such CTLs were obtained by priming mice with live allogeneic beta 2m- spleen cells or mutant lymphoma cells producing MHC class I protein but no detectable beta 2m. Although both beta 2m- and beta 2m-expressing lymphoma cells were rejected in allogeneic mice, only the former were efficient inducers of CTLs recognizing beta 2m- cells. These CTLs were MHC class I (H-2Kb or Db)-specific and CD8-dependent and did not require serum as a source of external beta 2m in the culture. They could be induced across major and minor histocompatibility barriers. The H-2-restricted CTLs generated in the latter case failed to kill the antigen-processing-deficient target RMA-S cells. The results show that MHC class I heavy chains in beta 2m- cells can be transported to the cell surface and act as antigens or antigen-presenting molecules to allospecific and MHC-restricted CTLs.
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