Serveur d'exploration Chloroquine

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Functional defects of NK cells treated with chloroquine mimic the lytic defects observed in perforin-deficient mice.

Identifieur interne : 002432 ( Main/Exploration ); précédent : 002431; suivant : 002433

Functional defects of NK cells treated with chloroquine mimic the lytic defects observed in perforin-deficient mice.

Auteurs : M. Austin Taylor [États-Unis] ; M. Bennett ; V. Kumar ; J D Schatzle

Source :

RBID : pubmed:11046034

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English descriptors

Abstract

NK cells are the primary effectors mediating acute rejection of incompatible bone marrow cell grafts. To reduce rejection, we evaluated the ability of chloroquine (CHQ) to prevent perforin-dependent NK cell activity. Perforin is a key cytotoxic component released from the lytic granules of activated NK cells. Generation of functional perforin requires an acidic protease activity that occurs in the secretory, lytic lysosomes. Our hypothesis was that CHQ, a lysosomotropic reagent, would raise the pH of the acidic compartment in which perforin is processed and thereby block perforin maturation and cytotoxicity. We have measured NK cytotoxicity in vivo by clearance of YAC-1 tumor cells from the lungs and by rejection of incompatible bone marrow transplants and in vitro by cytolysis of YAC-1 and Jurkat cells. The engraftment of bone marrow cells was monitored by recolonization of the spleen with hemopoietic cells from transplants of MHC class I-deficient bone marrow cells into lethally irradiated recipient mice. Transplant rejection was compared in two inbred strains of mice: 129, which apparently use perforin-dependent cytotoxicity, and C57BL/6, in which rejection can be perforin-independent. CHQ treatment reduced NK cell activity in 129 mice in which perforin is important for mediating rejection. CHQ affected the fraction of NK cell cytolysis that was Fas independent. In addition, we found that CHQ prevents perforin processing by LAK cells in vitro. These data indicate that CHQ may impair rejection of incompatible bone marrow transplants and other functions mediated by NK and cytotoxic T cells.

DOI: 10.4049/jimmunol.165.9.5048
PubMed: 11046034


Affiliations:


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<term>Animals</term>
<term>Bone Marrow Cells (drug effects)</term>
<term>Bone Marrow Cells (immunology)</term>
<term>Bone Marrow Transplantation (immunology)</term>
<term>Cell Movement (drug effects)</term>
<term>Cell Movement (immunology)</term>
<term>Cells, Cultured</term>
<term>Chloroquine (pharmacology)</term>
<term>Cytotoxicity, Immunologic (drug effects)</term>
<term>Cytotoxicity, Immunologic (genetics)</term>
<term>Fas Ligand Protein</term>
<term>Graft Rejection (genetics)</term>
<term>Graft Rejection (immunology)</term>
<term>Graft Rejection (prevention & control)</term>
<term>Histocompatibility Antigens Class I (genetics)</term>
<term>Humans</term>
<term>Immunosuppressive Agents (pharmacology)</term>
<term>Injections, Intravenous</term>
<term>Jurkat Cells</term>
<term>Killer Cells, Natural (drug effects)</term>
<term>Killer Cells, Natural (immunology)</term>
<term>Killer Cells, Natural (transplantation)</term>
<term>Ligands</term>
<term>Lung Neoplasms (immunology)</term>
<term>Lung Neoplasms (pathology)</term>
<term>Lung Neoplasms (prevention & control)</term>
<term>Membrane Glycoproteins (antagonists & inhibitors)</term>
<term>Membrane Glycoproteins (deficiency)</term>
<term>Membrane Glycoproteins (genetics)</term>
<term>Membrane Glycoproteins (metabolism)</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Inbred Strains</term>
<term>Mice, Knockout</term>
<term>Perforin</term>
<term>Pore Forming Cytotoxic Proteins</term>
<term>Protein Processing, Post-Translational (drug effects)</term>
<term>Protein Processing, Post-Translational (immunology)</term>
<term>Tumor Cells, Cultured (drug effects)</term>
<term>Tumor Cells, Cultured (immunology)</term>
<term>Tumor Cells, Cultured (pathology)</term>
<term>fas Receptor (metabolism)</term>
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<term>Antigènes d'histocompatibilité de classe I (génétique)</term>
<term>Cellules Jurkat</term>
<term>Cellules cancéreuses en culture ()</term>
<term>Cellules cancéreuses en culture (anatomopathologie)</term>
<term>Cellules cancéreuses en culture (immunologie)</term>
<term>Cellules cultivées</term>
<term>Cellules de la moelle osseuse ()</term>
<term>Cellules de la moelle osseuse (immunologie)</term>
<term>Cellules tueuses naturelles ()</term>
<term>Cellules tueuses naturelles (immunologie)</term>
<term>Cellules tueuses naturelles (transplantation)</term>
<term>Chloroquine (pharmacologie)</term>
<term>Cytotoxicité immunologique ()</term>
<term>Cytotoxicité immunologique (génétique)</term>
<term>Glycoprotéines membranaires (antagonistes et inhibiteurs)</term>
<term>Glycoprotéines membranaires (déficit)</term>
<term>Glycoprotéines membranaires (génétique)</term>
<term>Glycoprotéines membranaires (métabolisme)</term>
<term>Humains</term>
<term>Immunosuppresseurs (pharmacologie)</term>
<term>Injections veineuses</term>
<term>Ligand de Fas</term>
<term>Ligands</term>
<term>Lignées consanguines de souris</term>
<term>Maturation post-traductionnelle des protéines ()</term>
<term>Maturation post-traductionnelle des protéines (immunologie)</term>
<term>Mouvement cellulaire ()</term>
<term>Mouvement cellulaire (immunologie)</term>
<term>Perforine</term>
<term>Perforines</term>
<term>Rejet du greffon ()</term>
<term>Rejet du greffon (génétique)</term>
<term>Rejet du greffon (immunologie)</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Transplantation de moelle osseuse (immunologie)</term>
<term>Tumeurs du poumon ()</term>
<term>Tumeurs du poumon (anatomopathologie)</term>
<term>Tumeurs du poumon (immunologie)</term>
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<term>Membrane Glycoproteins</term>
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<term>Histocompatibility Antigens Class I</term>
<term>Membrane Glycoproteins</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Membrane Glycoproteins</term>
<term>fas Receptor</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Chloroquine</term>
<term>Immunosuppressive Agents</term>
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<term>Cellules cancéreuses en culture</term>
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<term>Glycoprotéines membranaires</term>
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<term>Bone Marrow Cells</term>
<term>Cell Movement</term>
<term>Cytotoxicity, Immunologic</term>
<term>Killer Cells, Natural</term>
<term>Protein Processing, Post-Translational</term>
<term>Tumor Cells, Cultured</term>
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<keywords scheme="MESH" qualifier="déficit" xml:lang="fr">
<term>Glycoprotéines membranaires</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Cytotoxicity, Immunologic</term>
<term>Graft Rejection</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Antigènes d'histocompatibilité de classe I</term>
<term>Cytotoxicité immunologique</term>
<term>Glycoprotéines membranaires</term>
<term>Rejet du greffon</term>
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<term>Cellules cancéreuses en culture</term>
<term>Cellules de la moelle osseuse</term>
<term>Cellules tueuses naturelles</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Mouvement cellulaire</term>
<term>Rejet du greffon</term>
<term>Transplantation de moelle osseuse</term>
<term>Tumeurs du poumon</term>
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<keywords scheme="MESH" qualifier="immunology" xml:lang="en">
<term>Bone Marrow Cells</term>
<term>Bone Marrow Transplantation</term>
<term>Cell Movement</term>
<term>Graft Rejection</term>
<term>Killer Cells, Natural</term>
<term>Lung Neoplasms</term>
<term>Protein Processing, Post-Translational</term>
<term>Tumor Cells, Cultured</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Glycoprotéines membranaires</term>
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<term>Lung Neoplasms</term>
<term>Tumor Cells, Cultured</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Chloroquine</term>
<term>Immunosuppresseurs</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Graft Rejection</term>
<term>Lung Neoplasms</term>
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<term>Animals</term>
<term>Cells, Cultured</term>
<term>Fas Ligand Protein</term>
<term>Humans</term>
<term>Injections, Intravenous</term>
<term>Jurkat Cells</term>
<term>Ligands</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Inbred Strains</term>
<term>Mice, Knockout</term>
<term>Perforin</term>
<term>Pore Forming Cytotoxic Proteins</term>
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<term>Cellules de la moelle osseuse</term>
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<term>Cytotoxicité immunologique</term>
<term>Humains</term>
<term>Injections veineuses</term>
<term>Ligand de Fas</term>
<term>Ligands</term>
<term>Lignées consanguines de souris</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Mouvement cellulaire</term>
<term>Perforine</term>
<term>Perforines</term>
<term>Rejet du greffon</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Tumeurs du poumon</term>
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<front>
<div type="abstract" xml:lang="en">NK cells are the primary effectors mediating acute rejection of incompatible bone marrow cell grafts. To reduce rejection, we evaluated the ability of chloroquine (CHQ) to prevent perforin-dependent NK cell activity. Perforin is a key cytotoxic component released from the lytic granules of activated NK cells. Generation of functional perforin requires an acidic protease activity that occurs in the secretory, lytic lysosomes. Our hypothesis was that CHQ, a lysosomotropic reagent, would raise the pH of the acidic compartment in which perforin is processed and thereby block perforin maturation and cytotoxicity. We have measured NK cytotoxicity in vivo by clearance of YAC-1 tumor cells from the lungs and by rejection of incompatible bone marrow transplants and in vitro by cytolysis of YAC-1 and Jurkat cells. The engraftment of bone marrow cells was monitored by recolonization of the spleen with hemopoietic cells from transplants of MHC class I-deficient bone marrow cells into lethally irradiated recipient mice. Transplant rejection was compared in two inbred strains of mice: 129, which apparently use perforin-dependent cytotoxicity, and C57BL/6, in which rejection can be perforin-independent. CHQ treatment reduced NK cell activity in 129 mice in which perforin is important for mediating rejection. CHQ affected the fraction of NK cell cytolysis that was Fas independent. In addition, we found that CHQ prevents perforin processing by LAK cells in vitro. These data indicate that CHQ may impair rejection of incompatible bone marrow transplants and other functions mediated by NK and cytotoxic T cells.</div>
</front>
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