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PubMed1980

Growth and differentiation in vitro of mast cells from mesenteric lymph nodes of Nippostrongylus brasiliensis-infected rats.

Intestinal mastocytosis begins to develop in rats, depending on the strain, at 14 (outbred Sprague-Dawley, SD) or 16 (inbred Lewis, L) days after infection with the nematode Nippostrongylus brasiliensis (Nippo). We have investigated in vitro mastopoiesis from mesenteric lymph node (MLN) cells cultured at various intervals post-infection, using a modified Marbrook liquid system. Greater increases in mast cells (MC) were observed in cultures of SD-MLN removed on day 14 after Nippo infection (IMLN-14) than from MLN removed from uninfected animals (NMLN): seven- to twenty-fold versus up to two-fold at 2 weeks and forty- to two hundred-fold versus up to twenty-fold at 4 weeks, respectively (P < 0.002). In contrast, similar differential increases in MC and histamine compared to uninfected controls, were demonstrated in 2 week cultures of MLN from L strain rats removed 17 (IMLN-17) and 20 (IMLN-20) but not 14 days after Nippo infection (P < 0.001). the presence of phytohaemagglutinin (PHA) in vitro was associated with enhanced MC differentiation from both IMLN-17 and IMLN-20, while worm antigen (Ag) stimulated mastopoiesis from IMLN-17, but suppressed the response from IMLN-20 (P < 0.02). Conditioned media (CM) prepared from unstimulated or PHA-stimulated IMLN-32 (i.e. removed 32 days after Nippo infection) caused significant mastopoiesis from NMLN in vitro when compared to no CM or Ag-stimulated CM (P < 0.01). Either MC precursors or cells which help MC differentiation exist in increased numbers in MLN of Nippo-infected rats. Mitogenic or antigenic stimulation modulates in vitro mastopoiesis, either directly or through soluble factors derivable from MLN cells. These in vitro methods can be utilized to understand further mechanisms of intestinal mastocytosis in the rat.

Animals↗
PubMed1980

Effect of serum from mice with dormant Friend leukemia viral infections on synthesis and modulation of erythroleukemia cell surface gp70.

Serum of mice with dormant Friend virus infections modulates the expression of cell surface antigens on Friend virus-transformed cells (FLC-745 cells). By radioimmunoassay, the modulated antigen was identified as virion gp70 of Friend leukemia virus. After two days of culture in medium containing 5% serum from mice with dormant Friend virus infections, the modulated cells expressed about 50% less surface gp70 than non-modulated cells cultured in 5% normal mouse serum. After 9 days in culture, the modulated cells expressed no surface gp70; however, these cells contained the same amount of internal gp70 as nonmodulated cells, indicating that gp70 was synthesized during the modulation period. Both modulated and nonmodulated cells grew equally well during the 9 days of culture. These results indicate that the effects of modulation of Friend virus-coded cell surface antigens are restricted to the cell surface.

Animals↗
PubMed1992

Psychological modulation of the delayed type hypersensitivity skin test.

Considerable data have demonstrated that psychological states can influence the immune system in animals. Whether human immune function can be intentionally modulated by the central nervous system is unknown. This article presents data from two studies that sought to demonstrate intentional modulation of the immune system by psychological interventions. It also discusses the methodological complexities involved with this type of research in humans.

Adult↗
PubMed2002

The HLA class I A locus affects susceptibility to type 1 diabetes.

Human leukocyte antigen A (HLA-A) genotypes were determined for samples from 283 multiplex, Caucasian, type 1 diabetes families from the Human Biological Data Interchange (HBDI) using an immobilized probe assay. Distribution of HLA-A alleles transmitted to patients was significantly different from that in affected family-based controls (AFBAC) (p = 0.004). Transmission disequilibrium test (TDT) analysis revealed differential transmission of several HLA-A alleles from parents to affected offspring. HLA class II DRB1 and DQB1 loci were also typed, allowing assignment of HLA-A alleles to haplotypes and calculation of linkage disequilibrium values. Some of the apparent effects of HLA-A alleles on type 1 diabetes susceptibility were attributable to linkage disequilibrium with DR and DQ alleles, although others were not. The differences in frequencies between patients and controls of alleles A*0101, A*2402, and A*3002 could not be explained by linkage disequilibrium alone. Our results suggest an important role for class I antigens in modulating susceptibility to type 1 diabetes.

Alleles↗
PubMed2004

Co-delivery of pro-apoptotic BAX with a DNA vaccine recruits dendritic cells and promotes efficacy of autoimmune diabetes prevention in mice.

Genetic vaccines encoding pancreatic beta cell antigens can prevent autoimmune (type 1) diabetes when delivered into murine model systems, but there is a need to improve their efficacy. Here, we investigated the effects of intramuscular delivery of DNA coding for the pro-apoptotic protein BAX together with an intracellular or a secreted form of the beta cell antigen glutamic acid decarboxylase (GAD) on diabetes onset and immune responses in non-obese diabetic (NOD) mice. We hypothesized that induction of apoptosis in vaccine-containing cells could lead to GAD tolerance and disease suppression. Remarkably, monitoring of spontaneous diabetes onset indicated that only delivery of DNA coding for secreted GAD and BAX resulted in significant prevention of the disease. Using GFP as a model plasmid-encoded antigen revealed that co-delivery of BAX resulted in the recruitment of GFP-containing dendritic cells (DCs) in the draining lymph nodes and spleen of NOD mice. Furthermore, data indicated that subcellular localization of GAD had an effect on both the number and function of antigen presenting cells (APCs) recruited by BAX as well as on IFN-gamma secretion, and that diabetes suppression was unlikely to be caused by increased T helper 2 (Th2)-like activity. Our results indicate that, under certain conditions, co-delivery of DNA encoding BAX can improve the efficacy of genetic vaccination for prevention of pathogenic autoimmunity via a mechanism likely to involve modulation of antigen presenting cell function. In addition, our data also suggest that properties associated with subcellular localization of an antigen in apoptotic cells can have a significant effect on induced immune responses.

Animals↗
PubMed1995

Defective phosphorylation and hyaluronate binding of CD44 with point mutations in the cytoplasmic domain.

CD44 is a cell surface adhesion molecule that plays a role in leukocyte extravasation, leukopoiesis, T lymphocyte activation, and tumor metastasis. The principal known ligand for CD44 is the glycosaminoglycan hyaluronate, (HA), a major constituent of extracellular matrices. CD44 expression is required but is not sufficient to confer cellular adhesion to HA, suggesting that the adhesion function of the receptor is regulated. We recently demonstrated that CD44 in primary leukocytes is phosphorylated in a cell type- and activation state-dependent fashion. In this study we demonstrate that serines 325 and 327 within the cytoplasmic domain of CD44 are required for the constitutive phosphorylation of CD44 in T cells. Furthermore, we demonstrate that cells expressing mutated CD44 containing a serine to glycine substitution at position 325 or a serine to alanine substitution at amino acid 327 are defective in HA binding, CD44-mediated adhesion of T cells to smooth muscle cells, as well as ligand-induced receptor modulation. The effect of these mutations can be partially reversed by a monoclonal anti-CD44 antibody that enhances CD44-mediated HA binding.

Amino Acid Sequence↗
PubMed2004

Unique modifications with phosphocholine and phosphoethanolamine define alternate antigenic forms of Neisseria gonorrhoeae type IV pili.

Several major bacterial pathogens and related commensal species colonizing the human mucosa express phosphocholine (PC) at their cell surfaces. PC appears to impact host-microbe biology by serving as a ligand for both C-reactive protein and the receptor for platelet-activating factor. Type IV pili of Neisseria gonorrhoeae (Ng) and Neisseria meningitidis, filamentous protein structures critical to the colonization of their human hosts, are known to react variably with monoclonal antibodies recognizing a PC epitope. However, the structural basis for this reactivity has remained elusive. To address this matter, we exploited the finding that the PilE pilin subunit in Ng mutants lacking the PilV protein acquired the PC epitope independent of changes in pilin primary structure. Specifically, we show by using mass spectrometry that PilE derived from the pilV background is composed of a mixture of subunits bearing O-linked forms of either phosphoethanolamine (PE) or PC at the same residue, whereas the wild-type background carries only PE at that same site. Therefore, PilV can influence pilin structure and antigenicity by modulating the incorporation of these alternative modifications. The disaccharide covalently linked to Ng pilin was also characterized because it is present on the same peptides bearing the PE and PC modifications and, contrary to previous reports, was found to be linked by means of 2,4-diacetamido-2,4,6-trideoxyhexose. Taken together, these findings provide new insights into Ng type IV pilus structure and antigenicity and resolve long-standing issues regarding the nature of both the PC epitope and the pilin glycan.

Amino Acid Sequence↗
PubMed2005

The putative mechanism of the immunomodulating effect of HLA-DR shared allogeneic blood transfusions on the alloimmune response.

Pretransplant blood transfusions have shown to improve organ allograft survival. However, the immunologic mechanism leading to this beneficial effect in clinical transplantation is still not clear. The observation that blood transfusions sharing an HLA-DR antigen with the recipient are more effective than HLA mismatched transfusions has led to the hypothesis that CD4(+) regulatory T (Treg) cells that recognize a foreign peptide in the context of the shared HLA-DR molecule play an important role in down-regulation of the immune response toward the graft. Available experimental evidence supports this hypothesis. Furthermore, these CD4(+) Treg cells are able to modulate antigen-presenting cells, which in their turn will induce Treg cells. As long as clinical transplantation tolerance by blood transfusions is not a reality, further studies on the mechanisms of the beneficial effect of pretransplant allogeneic blood transfusions are needed to obtain an effective protocol for the induction of clinically relevant Treg cells.

Blood Transfusion↗
PubMed1997

Microencapsulation of antigens using biodegradable polyesters: facts and phantasies.

New vaccination approaches and new delivery systems have been subject of intensive research activities recently. Controlled release vaccine delivery systems depend on the microencapsulation of antigens into biodegradable polymers, yielding small spherical polymeric particles, in the size range of 1-100 microns. By manipulating the micromorphology of the microparticles and degradation properties of the polymer either continuous or pulsatile release patterns can be adjusted. As biodegradable polymers mainly copolymers of lactic- and glycolic acid have been utilized, since these materials are known to be biocompatible and non-toxic. Apart from modulation of antigen release, an improvement of the adjuvant effect and an increase of in vitro (shelf-life) and in vivo stability of the antigen are issues of general interest with respect to parenteral vaccine delivery systems. Using different microparticles that release antigens in a pulsatile pattern at predetermined timepoints one hopes to induce protective immunity by a single administration of the vaccine delivery system. Using tetanus toxoid (TT) as a model antigen we have examined the stability during preparation, in vitro release and storage of TT microparticles. TT is a complex protein mixture sensitive to changes in pH conditions (pH < 5) and to thermal stress. TT microparticles can be prepared by a W/O/W double emulsion technique with satisfactory encapsulation efficiencies in good yields. In accordance with other investigators we observe an adjuvant effect of TT microspheres in mice upon sc administration leading to a long-lasting antibody response. In challenge experiments we could demonstrate a protective effect. The issue of an ideal release pattern remains open, since a boosting of the antibody titers during the bioerosion of the TT microspheres was not observed, possibly due to desactivation of TT in the degrading microspheres.

Animals↗
PubMed1984

Modulation of T-cell antigen receptor on lymphocyte membrane.

A mouse monoclonal antibody, Mo. Ab. 108.45, detecting cell-surface determinants associated with the T-cell receptor for alloantigen was produced by immunizing mice with an alloreactive human T-cell clone and fusing the splenocytes with the NS1 plasmocytoma. This Mo. Ab. reacts with the immunizing T-cell clone but not with autologous or allogeneic lymphocytes, lymphoblasts or monocytes; stimulates the proliferation of the immunizing T cells in the absence of the alloantigen; inhibits the response to the specific stimulator; and precipitates a disulfied linked heterodimer composed of two distinct glycoproteins of molecular weights 40000 and 46000. The receptor molecule detected by Mo. Ab. 108.45 modulates on the surface of the cells, reaching the highest levels 5 days following exposure to the specific stimulator. The receptor-associated molecule detected by Mo. Ab. 108.45 was expressed by T-cell clones obtained independently in two different mixed lymphocyte cultures between the same responder and stimulator.

Antibodies, Monoclonal↗
PubMed2001

Ovine IFN-tau modulates the expression of MHC antigens on murine cerebrovascular endothelial cells and inhibits replication of Theiler's virus.

Interferon-beta (IFN-beta) has been used successfully to treat patients with relapsing-remitting multiple sclerosis (MS). IFN-tau is a new class of type I IFN that is secreted by the trophoblast and is the signal for maternal recognition of pregnancy in sheep. IFN-tau has potent immunosuppressive and antiviral activities similar to other type I IFN but is less cytotoxic than IFN-alpha/beta. The current investigation concerns the effect of recombinant ovine IFN-tau (rOvIFN-tau) on the modulation of MHC class I and II expression on cloned mouse cerebrovascular endothelial (CVE) cells. IFN-tau induced tyrosine phosphorylation of Stat1 and upregulated the expression of MHC class I on CVE. One proposed action by which type I IFN reduce the relapse rate in MS is via interference with IFN-gamma-induced MHC class II expression. IFN-tau was shown to downregulate IFN-gamma-induced MHC class II expression on CVE and, hence, may be of potential therapeutic value in downregulating inflammation in the central nervous system (CNS). IFN-tau did not upregulate the expression of MHC class II on CVE. IFN-tau also inhibited the replication of Theiler's virus in CVE. These in vitro results suggest that IFN-tau may be of therapeutic value in the treatment of virus-induced demyelinating disease.

Animals↗
PubMed1995

Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand.

We demonstrate that cognate peptide ligands altered at T cell receptor (TCR) contact residues and bound to class II major histocompatability complex can change the cytokine pattern of mature T cell clones. Myelin basic protein peptide 85-99-reactive Th0 T cell clones were stimulated with altered peptide ligands, which acted both as TCR antagonist and induced new mRNA synthesis and protein secretion of TGF-beta 1, while no longer inducing mRNA synthesis or protein secretion of IL-2, IL-4, IL-10, and IFN gamma. The modified peptides failed to induce a detectable calcium flux, p56lck activation, or thymidine incorporation, yet triggered nearly equal amounts of IL-4 secretion in the presence of ionomycin. Antigen-induced modulation of T cell cytokine secretion may be important in regulating the immune response.

Base Sequence↗
PubMed1990

Activity of herpes simplex virus type 1-specified glycoprotein C antigenic site II epitopes reversibly modulated by peripheral fucose or galactose units of glycoprotein oligosaccharides.

We have previously shown that the herpes simplex virus type 1 (HSV-1)-specified glycoprotein C (gC-1) produced in epitheloid cells contains epitopes of peptide nature, which are dependent on galactose of oligosaccharides for their expression. In the present communication we report that these epitopes are expressed in a mouse neuroblastoma cell line (C1300) with low levels of galactosyl transferases. However, in place of galactose the glycoprotein from C1300 cells was found to contain oligosaccharides with additional fucose units. Fucosidase treatment, but not galactosidase treatment, abolished the antigenic activity of the carbohydrate-dependent epitopes. Altogether the results indicated that the carbohydrate-dependent epitopes of gC-1 from C1300 cells were stabilized by peripheral sugars of N-linked oligosaccharides rather than O-linked ones and that fucose could substitute for terminal galactose in promoting the activity of the carbohydrate-dependent epitopes. This is the first demonstration of the involvement of fucose in the establishment of a carbohydrate-dependent epitope of peptide nature. The results also demonstrated that reversible carbohydrate-peptide interactions were responsible for the activity of the carbohydrate-dependent epitopes.

Animals↗
PubMed1985

Modulation of Ia and photoreactive antigen on antigen-presenting cells: fun with a photoprobe.

To identify the antigen-specific recognition complex containing elements from T cells and antigen-presenting cells (APC), a photoactivatable antigen system was developed which could potentially crosslink the complex during the specific cellular responses. In this paper we describe the development of this system using murine T-cell hybridomas responding to stimulator cells chemically conjugated with N-hydroxysuccinimidyl 4-azidobenzoate (HSAB) and genetically restricted by I-Ad. In initial experiments it was found that several I-Ad-positive B-cell lines were nonstimulatory when coupled with HSAB, but that I-Ad-positive P388D1 macrophage-like cells were efficient stimulators of HSAB-specific T-cell responses. These results suggested that the relevant HSAB coupled surface structure was not likely I-Ad. To substantiate this point, Ia-positive or Ia-negative P388D1 cells were initially coupled with HSAB and the expression of Ia was modulated by the addition and withdrawal of Con A-stimulated spleen cell supernatant fluid through several days of culture. Under these conditions, efficient stimulation was only observed when Ia was expressed, although the HSAB antigen was continuously present. In other experiments it was found that exposure of HSAB-coupled APC to light selectively eliminated their stimulatory capacity for HSAB-specific T hybridomas, suggesting that the light-induced crosslinking by HSAB directly eliminates the antigenic determinant. This antigen system allows a unique opportunity to manipulate the antigen during specific cellular interactions, and to introduce covalent crosslinking of the specific antigen recognition complex that may allow its isolation and characterization.

Animals↗
PubMed1987

Blood group ABO and Lewis antigen expression during neoplastic progression of human urothelium. Immunohistochemical study of type 1 chain structures.

The deletion of blood group ABO antigen expression in bladder carcinoma has attracted attention because of its potential as a prognostic parameter. Based on recently produced monoclonal antibodies against blood group antigens, it has become possible to elucidate the carcinoma-associated modulation of these antigens at a molecular level. In this study we have used a panel of monoclonal antibodies (H, Lea, Leb, A, ALeb) that are specific to type 1 chain structures. By the use of an immunohistochemical method, the histologic and cytologic location of these antigens in the urothelium was studied in 25 biopsies from transitional cell carcinomas and compared to 21 previously examined normal biopsies. Urothelial blood group reactivity was compared to Lewis and secretor status. The authors found a series of events associated with neoplastic progression of noninvasive urothelium: a disruption of the orderly stratification of blood group antigens in different cell layers; cytostructural relocation of cytoplasmic antigens to the cell surface; loss of correlation between urothelial blood group antigens and secretor status; and gradual deletion of antigens. In the invasive tissue these events were followed by a total deletion of A and H isoantigens and uniform expression of Lewis b and sialyted Lewis a antigen. These findings indicate that there is a complex modulation of blood group antigen biosynthesis associated with the neoplastic progression of the human urothelium.

ABO Blood-Group System↗
PubMed1995

The function of invariant chain in class II-restricted antigen presentation.

The role of invariant chain (Ii) in antigen presentation has been studied using two independent approaches. The first was to reconstitute cell lines with class II molecules and various forms of the Ii; the second has been to generate mice that lack functional expression of the Ii gene (Ii.). Both types of studies show that Ii facilitates assembly of class II molecules in the endoplasmic reticulum (ER), chaperones or retains properly folded class II complexes through endosomal compartments, and finally, serves as a T-cell ligand. How Ii facilitates assembly of antigenic class II-peptide complexes is less clear and seems to depend on a number of factors reviewed here: the antigen and epitope studied; the route and dose by which antigen is administered; the form of Ii present; and the responding T cell used in the experiment. During assembly of the class II-peptide complex, Ii may facilitate this process in a number of ways: specifically, by increasing the amount of class II available in endosomal vesicles; changing access or retention of class II molecules in the endosomal pathway; facilitating peptide exchange during CLIP dissociation, or finally, by modulating the antigen processing environment in the cell. In summary, we propose that instead of playing just one role in assembling the class II-peptide complex, Ii may perform all of the above described activities, functioning in different capacities along the pathway of antigen presentation.

Animals↗
PubMed1989

The molecular basis of granuloma formation in schistosomiasis. II. Analogies of a T cell-derived suppressor effector factor to the T cell receptor.

During Schistosoma mansoni infection, Ts cells regulate granulomatous modulation via antigenically and genetically restricted suppressor inducer and suppressor effector factors. The T suppressor effector factor (TseF) directly suppresses granuloma formation both in vitro and in vivo. In this study, we probe the molecular basis of these TseF properties. Using techniques of heterodimeric chain reduction with DTT and in vitro functional complementation, chimeric molecules were constructed. By analyzing genetic restrictions, antigenic specificities, and phenotypic markers, the contributions of the component chains to 72 kDa TseF reactivity were determined. One chain bore an Ag receptor and imparted antigenic specificity. The other chain bore an IJ determinant, a TCR beta-chain allotypic determinant, a suppressor effector phenotypic determinant, and imparted functional genetic restriction. Functional activity required covalent, probably sulfhydryl mediated, linkage as succinylation prevented the separated component chains from reconstituting functional activity. Additional studies demonstrated that anti-serum directed against either the T cell receptor or the T3 epsilon-chain could abrogate functional activity. However, TseF bore no T3 epsilon-chain phenotypic marker per se suggesting that TseF effects T lymphocytes via transmembrane signal transduction. These studies suggest that a regulatory network is operative in granuloma modulation. This regulatory network is mediated by a soluble TseF that bears significant structural homologies to the classic TCR.

Animals↗
PubMed1995

CD8 modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes.

Thymocytes and class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes express predominantly heterodimeric alpha/beta CD8. By interacting with non-polymorphic regions of MHC class I molecules CD8 can mediate adhesion or by binding the same MHC molecules that interact with the T-cell antigen receptor (TCR) function as coreceptor in TCR-ligand binding and T-cell activation. Using TCR photoaffinity labelling with a soluble, monomeric photoreactive H-2Kd-peptide derivative complex, we report here that the avidity of TCR-ligand interactions on cloned cytotoxic T cells is very greatly strengthened by CD8. This is primarily explained by coordinate binding of ligand molecules by CD8 and TCR, because substitution of Asp 227 of Kd with Lys severely impaired the TCR-ligand binding on CD8+, but not CD8- cells. Kinetic studies on CD8+ and CD8- cells further showed that CD8 imposes distinct dynamics and a remarkable temperature dependence on TCR-ligand interactions. We propose that the ability of CD8 to act as coreceptor can be modulated by CD8-TCR interactions.

Amino Acid Sequence↗