Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we review our current results studying B cells as APC and the mechanisms by which processed antigen is transported to and held on the cell surface for recognition by the specific T cell along with the MHC class II molecules. These studies were carried out using the globular protein cytochrome c as antigen for which the T-cell antigenic determinant was localized to a C-terminal 10-amino acid peptide fragment. For certain analyses, native cytochrome c or antigenic peptide fragments were covalently coupled to antibodies directed toward B-cell surface structures, allowing the targeting of antigen to the APC surface. Our findings indicate that all B cells function as APC and that the APC function is not differentially regulated in defined B-cell subpopulations. Using cytochrome c-antibody conjugates, it was shown that the surface Ig plays two significant roles in augmenting the B-cell APC function following antigen binding: signalling for enhanced APC function and concentrating antigen for subsequent internalization and processing. Both IgM and IgD appear to function identically in facilitating antigen processing in both immune and nonimmune B-cell populations. Furthermore, the surface Ig does not appear to be specially differentiated to function in concentrating antigen, as antigen artificially bound to other B-cell surface structures including MHC class I and class II molecules is also effectively presented. Lastly, evidence is presented that a previously described B-cell activating factor activity is strongly associated with the membranes of activated but not unactivated helper T cells, providing a mechanism by which the T-cell helper function can be focused on the specific antigen-presenting B cell. Concerning the mechanism by which processed antigen is presented at the B-cell surface, evidence is presented suggesting a role of peptide-binding chaperone proteins which may function to transport peptide to the APC surface and facilitate its association with the appropriate Ia. One candidate protein, PBP72/74, is described which binds peptides but not native antigens, is a member of the hsp70 family and appears to play a role in antigen presentation by the ability of antisera raised against it to block APC functions. Peptide-antibody conjugates were used to explore the spacial restrictions on MHC-restricted peptide presentation and it was shown that peptides covalently coupled to antibodies specific for Ig, class I or class II molecules are effective antigens in vitro even in the absence of processing.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antigen-presenting function of B lymphocytes. 307 88

Previously, we reported that killing tumor cells in vivo with the HSV thymidine kinase/ganciclovir system generates potent antitumor immunity, determined in part by the mechanism by which the cells die and by the levels of inducible heat shock protein (hsp) expression induced during the process of cell death. Here, we show that induction of hsp70 expression induces an infiltrate of T cells, macrophages, and predominantly dendritic cells (DCs) into the tumors as well as an intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12) and enhances immunogenicity via a T cell-mediated mechanism. In addition, the protection conferred by hsp70 is both tumor and cell specific. We also demonstrate that hsp70 targets immature APC to make them significantly more able to capture Ags. This is likely to optimize cross-priming of the infiltrating APC with tumor Ags, which are simultaneously being released by the dying cells. In addition, using an Myc epitope-tagged hsp70 expression vector, we present evidence that hsp70 released from dying tumor cells is taken up directly into DCs and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken together, our data suggest that hsp70 induction serves to signal the immune system of the presence of an immunologically relevant (dangerous) situation against which an immune reaction should be raised.
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PMID:Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. 1041 40

NO is a cytotoxic and immunomodulatory cytokine produced by macrophages and dendritic cells. We show that stimulation of murine and human macrophages with the heat shock proteins gp96 and hsp70 results in induction of inducible NO synthase and the production of NO. The release of NO by monocytes exposed to hsp60 has been documented previously. Immature, but not mature, dendritic cells respond in the same manner. The activity of heat shock proteins is relatively unaffected by an antagonist of LPS, and is abrogated by heat denaturation. Macrophages have been shown previously to produce NO in response to stimulation with IFN-gamma; stimulation of macrophages with mixtures of IFN-gamma and gp96 or hsp70 leads to a synergistic production of NO. The present observations extend the roles of these heat shock proteins in innate immune responses to another potent and highly conserved function of APC.
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PMID:Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. 1188 72

Previous work has suggested that the peptide-carrier, heat-shock protein (hsp)70, could directly activate APC. Here we show that this ability is related to endotoxin contamination of the human rhsp70 produced in Escherichia coli. Hence, the ability of 1-3 microg/ml of rhsp70 to induce the maturation of human monocyte-derived DC is abrogated in the presence of the LPS-antagonist polymyxin B or when the rhsp70 contains less than 60 IU/mg endotoxin. Such a level of contamination of the rhsp70 is, however, sufficient - in the presence of soluble rCD14, the LPS co-receptor - to induce cytokine secretion from monocytes and DC, despite the presence of polymyxin B. However, when endotoxin contamination is below 10 IU/mg, rhsp70 does not induce cytokine secretion - even in the presence of soluble rCD14 - or activate p38 mitogen-activated protein kinase signaling pathways, thus showing that an "endotoxin free" hsp70 does not activate APC.
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PMID:Endotoxin-free heat-shock protein 70 fails to induce APC activation. 1251 64

Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-alpha. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.
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PMID:Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas. 1695 82

CD40 has been suggested previously to be a receptor for mammalian murine hsc73 (hsp70). We have examined, in vitro and in vivo, the role of CD40 in the interaction of murine dendritic cells and macrophages with hsp70, using several independent parameters including cell surface binding, translocation of NF-kappaB, stimulation of release of TNF-alpha, representation of hsp70-chaperoned peptides, and priming of CD8(+) T cells. The various consequences of hsp70-APC interaction were compared between CD40(+/+) and CD40(-/-) mice and were found to be identical in kinetics and magnitude. These data strongly indicate that all known effects of mammalian hsp70 on APCs are mediated in a CD40-independent manner. In light of the earlier demonstration that mycobacterial hsp70 binds murine CD40 and stimulates the APCs through it, our data indicate that CD40 can discriminate between self and mycobacterial hsp70 and is thus a receptor for patterns associated with microbial pathogens.
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PMID:CD40-independent engagement of mammalian hsp70 by antigen-presenting cells. 1945 80