Conny van Holten - Academia.edu (original) (raw)

Papers by Conny van Holten

Research paper thumbnail of Generation and selection of monoclonal antibodies to variants of α1-antitrypsin specific for one single amino acid using synthetic peptides: Importance of conjugation of synthetic determinants

Research paper thumbnail of Peptide-induced memory (IgG) response requires covalent linkage of a B-cell epitope and a T-cell epitope

Research paper thumbnail of Recombinant lactobacillus strains secreting myelin antigens for mucosal tolerance induction in autoimmune disease

Journal of Neuroimmunology, 1998

Chronic antointmunc diseases such as mullip]e sclerosis, diabetes and rheumatoid arthritis arc ca... more Chronic antointmunc diseases such as mullip]e sclerosis, diabetes and rheumatoid arthritis arc caused by CD4+ Thl ceils. Th2 cells antagonize Thl ftmclions and shown It prevent or cure aulohnl'ouno disease. Nevcrthcless. recent sludies showed clear exceptions It Ihis concept. In addition, the cenlnd nervous systcnt cnvirornncnt was shown It control elf curer CD4+ T-cell eylokinc profile in EAE. Taken together, these publications imply that distinct anligen-specific T-cells can be influenced by in vivo cffeclors other than their spccific anligen. flint such inllucnce may be manifested by ahcrcd cytokinc secretion, and that this ahcration may detcrndne whether autoimmune-dirccted T-cells would bc pathogenic or pmlcctive. Wc invcsligated whelhcr lbur difl~rent neuropeptidcs -Smnatostatia. Caleitonin-gcne-relatcd-peptide, Neuropcptide Y and Subslaacc Pcould directly induce cylokine secretion from distinct Thl and Tb2 antigenspecific autoimmune-relaled T-ceils. All lout ncuropcptidcs were reported Io have spccific T cull expressed receptors. The rcsuhs of the present study show that the neuropcptides, in Iho absence of addilionai molecules, induced the secretion of both lypicul and atypical cylokines frmn distincl ThO. Th[ and Th2 autoinmtunc-relaled T-cells. Tbus, neuropeptidcs may in fluencc T-cells in a way that will break their commitmenl It a distinct Thl or Th2 profile, and ntay theroby afl~ct their dcsliny.

Research paper thumbnail of Peptide-induced memory (IgG) response, cross-reactive with native proteins, requires covalent linkage of a specific B cell epitope with a T cell epitope

European Journal of Immunology, 1993

In order to raise antibodies synthetic peptides are often coupled to a carrier protein to provide... more In order to raise antibodies synthetic peptides are often coupled to a carrier protein to provide the necessary T cell determinants. Alternatively, a short synthetic determinant with a distinct sequence motif which can be presented by major histocompatibility complex (MHC) class I1 toT cells, can be linked directly to a B cell epitope. Recently, it has been suggested that covalent linkage between a class 11-presentable T helper peptide and a B cell epitope is not required to induce antibodies against a B cell determinant (Sarobe et al., Eur. J. Immunol. 1991.21: 1555).Therefore, we investigated the ability of an H-2d-restricted T cell determinant (AA 11 1-120 FERFEIFPKEK) from the influenza virus hemagglutinin, to support B cell responses to different proven B cell determinant peptides, derived from human al-antitrypsin. Antibodies against B cell epitopes crossreactive with native al-antitrypsin could be raised only when these B epitope peptides were covalently coupled to the T cell determinant through a peptide bond. No antibodies were raised against the B cell epitope when the free peptides (T and B cell epitopes) were just mixed or when the T cell epitope was conjugated via m-maleimidobenzoyl succinimide ester or bis-maleimidohexane to the B cell determinant. Antibodies against the T cell determinant were raised in all cases, regardless of the mode of presentation: just mixed with or covalently coupled to the B cell determinant. The results indicate that a covalent bond between T cell and B cell determinants in general is needed to induce anti B cell determinant antibodies cross-reactive with the native protein. Abbreviations: TD: T cell determinant BD: B cell determinant MBS: m-Maleimidobenzoyl succinimide ester al-AT aIantitrypsin

Research paper thumbnail of Differential rat T cell recognition of cathepsin D-released fragments of mycobacterial 65 kDa heat-shock protein after immunization with either the recombinant protein or whole mycobacteria

International Immunology, 1994

T cells specific for the mycobacterial 65 kDa heat-shock protein (hsp65) play a pivotal role in t... more T cells specific for the mycobacterial 65 kDa heat-shock protein (hsp65) play a pivotal role in the development of adjuvant arthritis (AA) in Lewis rats. Upon adoptive transfer, CD4+ T cells recognizing a particular hsp65 epitope trigger the onset of disease. Activation of hsp65-reactive T cells can be achieved by immunization with heat-killed mycobacteria in mineral oil--complete Freund's adjuvant (CFA)--or with purified recombinant hsp65. Arthritis, however, will only develop after immunization with CFA. In fact, preimmunization with hsp65 protects against any subsequent attempt to induce AA. In this study, we examined polyclonal lymph node cell responses in Lewis rats, immunized with either CFA or purified recombinant hsp65 in incomplete Freund's adjuvant, to a set of hsp65 fragments generated by a mild digestion with cathepsin D. Proliferative responses to several hsp65 fragments varied with the type of antigen used for immunization. A cathepsin D-released fragment, identified as residues 376-408, preferentially triggered proliferation of rat T cells after hsp65 immunization. Preimmunization of Lewis rats with this peptide delayed the onset and reduced the severity of AA. Preimmunization with another fragment which was preferentially recognized after CFA immunization, representing residues 40-60, did not have such a protective effect. Our findings suggest the presence of mycobacterial hsp65 determinants that selectively trigger AA-regulating T cells and illustrate that cathepsin D may be used as an experimental tool to generate such determinants.

Research paper thumbnail of Generation and selection of monoclonal antibodies to variants of α1-antitrypsin specific for one single amino acid using synthetic peptides: Importance of conjugation of synthetic determinants

Research paper thumbnail of Peptide-induced memory (IgG) response requires covalent linkage of a B-cell epitope and a T-cell epitope

Research paper thumbnail of Recombinant lactobacillus strains secreting myelin antigens for mucosal tolerance induction in autoimmune disease

Journal of Neuroimmunology, 1998

Chronic antointmunc diseases such as mullip]e sclerosis, diabetes and rheumatoid arthritis arc ca... more Chronic antointmunc diseases such as mullip]e sclerosis, diabetes and rheumatoid arthritis arc caused by CD4+ Thl ceils. Th2 cells antagonize Thl ftmclions and shown It prevent or cure aulohnl'ouno disease. Nevcrthcless. recent sludies showed clear exceptions It Ihis concept. In addition, the cenlnd nervous systcnt cnvirornncnt was shown It control elf curer CD4+ T-cell eylokinc profile in EAE. Taken together, these publications imply that distinct anligen-specific T-cells can be influenced by in vivo cffeclors other than their spccific anligen. flint such inllucnce may be manifested by ahcrcd cytokinc secretion, and that this ahcration may detcrndne whether autoimmune-dirccted T-cells would bc pathogenic or pmlcctive. Wc invcsligated whelhcr lbur difl~rent neuropeptidcs -Smnatostatia. Caleitonin-gcne-relatcd-peptide, Neuropcptide Y and Subslaacc Pcould directly induce cylokine secretion from distinct Thl and Tb2 antigenspecific autoimmune-relaled T-ceils. All lout ncuropcptidcs were reported Io have spccific T cull expressed receptors. The rcsuhs of the present study show that the neuropcptides, in Iho absence of addilionai molecules, induced the secretion of both lypicul and atypical cylokines frmn distincl ThO. Th[ and Th2 autoinmtunc-relaled T-cells. Tbus, neuropeptidcs may in fluencc T-cells in a way that will break their commitmenl It a distinct Thl or Th2 profile, and ntay theroby afl~ct their dcsliny.

Research paper thumbnail of Peptide-induced memory (IgG) response, cross-reactive with native proteins, requires covalent linkage of a specific B cell epitope with a T cell epitope

European Journal of Immunology, 1993

In order to raise antibodies synthetic peptides are often coupled to a carrier protein to provide... more In order to raise antibodies synthetic peptides are often coupled to a carrier protein to provide the necessary T cell determinants. Alternatively, a short synthetic determinant with a distinct sequence motif which can be presented by major histocompatibility complex (MHC) class I1 toT cells, can be linked directly to a B cell epitope. Recently, it has been suggested that covalent linkage between a class 11-presentable T helper peptide and a B cell epitope is not required to induce antibodies against a B cell determinant (Sarobe et al., Eur. J. Immunol. 1991.21: 1555).Therefore, we investigated the ability of an H-2d-restricted T cell determinant (AA 11 1-120 FERFEIFPKEK) from the influenza virus hemagglutinin, to support B cell responses to different proven B cell determinant peptides, derived from human al-antitrypsin. Antibodies against B cell epitopes crossreactive with native al-antitrypsin could be raised only when these B epitope peptides were covalently coupled to the T cell determinant through a peptide bond. No antibodies were raised against the B cell epitope when the free peptides (T and B cell epitopes) were just mixed or when the T cell epitope was conjugated via m-maleimidobenzoyl succinimide ester or bis-maleimidohexane to the B cell determinant. Antibodies against the T cell determinant were raised in all cases, regardless of the mode of presentation: just mixed with or covalently coupled to the B cell determinant. The results indicate that a covalent bond between T cell and B cell determinants in general is needed to induce anti B cell determinant antibodies cross-reactive with the native protein. Abbreviations: TD: T cell determinant BD: B cell determinant MBS: m-Maleimidobenzoyl succinimide ester al-AT aIantitrypsin

Research paper thumbnail of Differential rat T cell recognition of cathepsin D-released fragments of mycobacterial 65 kDa heat-shock protein after immunization with either the recombinant protein or whole mycobacteria

International Immunology, 1994

T cells specific for the mycobacterial 65 kDa heat-shock protein (hsp65) play a pivotal role in t... more T cells specific for the mycobacterial 65 kDa heat-shock protein (hsp65) play a pivotal role in the development of adjuvant arthritis (AA) in Lewis rats. Upon adoptive transfer, CD4+ T cells recognizing a particular hsp65 epitope trigger the onset of disease. Activation of hsp65-reactive T cells can be achieved by immunization with heat-killed mycobacteria in mineral oil--complete Freund's adjuvant (CFA)--or with purified recombinant hsp65. Arthritis, however, will only develop after immunization with CFA. In fact, preimmunization with hsp65 protects against any subsequent attempt to induce AA. In this study, we examined polyclonal lymph node cell responses in Lewis rats, immunized with either CFA or purified recombinant hsp65 in incomplete Freund's adjuvant, to a set of hsp65 fragments generated by a mild digestion with cathepsin D. Proliferative responses to several hsp65 fragments varied with the type of antigen used for immunization. A cathepsin D-released fragment, identified as residues 376-408, preferentially triggered proliferation of rat T cells after hsp65 immunization. Preimmunization of Lewis rats with this peptide delayed the onset and reduced the severity of AA. Preimmunization with another fragment which was preferentially recognized after CFA immunization, representing residues 40-60, did not have such a protective effect. Our findings suggest the presence of mycobacterial hsp65 determinants that selectively trigger AA-regulating T cells and illustrate that cathepsin D may be used as an experimental tool to generate such determinants.