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Biomedical subjects

A Svejgaard

Publications and source records attributed to A Svejgaard.

At least 109 records · Page 6Linked to original sources
PubMed1996

IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis.

Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (<5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.

CD18 Antigens↗
PubMed1996

Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide.

A cytotoxic T lymphocyte (CTL) clone generated in vitro from the peripheral blood of a healthy HLA-A2-positive individual against a synthetic p53 protein-derived wild-type peptide (L9V) was shown to kill squamous carcinoma cell lines derived from two head and neck carcinomas, which expressed mutant p53 genes, in a L9V/HLA-A2 specific and restricted fashion. Thus, the normal tolerance against endogenously processed p53 protein-derived self-epitopes can be broken by peptide-specific in vitro priming. p53 protein-derived wild-type peptides might thus represent tumor associated target molecules for immunotherapeutical approaches.

Carcinoma, Squamous Cell↗
PubMed1996

The progeny of a single virgin B cell predominates the human recall B cell response to the capsular polysaccharide of Haemophilus influenzae type b.

Restricted V region diversity is a key feature of Abs to many haptens and simple polysaccharides. Two possible mechanisms exist: 1) selection of many clonally unrelated B cells using very similar or identical VDJ and VJ rearrangements; and 2) selection of a heavily expanded progeny of few virgin B cells. How many virgin B cells eventually give rise to the total Ab response to a simple Ag is a fundamental immunologic question. In this report, we address this question in human adults by analyzing the rearranged VkappaJkappa genes of B cells responding to a single dose of the capsular polysaccharide of Haemophilus influenzae type b coupled to tetanus toxoid. We combined affinity purification of circulating vaccine-induced Ab-secreting cells with PCR amplification of cDNA followed by cloning and sequencing. Forty-eight and 42 kappa VJ gene transcripts were analyzed from two adults, respectively. Both individuals used extremely restricted repertoires with >90% of the cells using a single Vkappa gene rearranged to a single Jkappa gene. Despite the fact that the Ab responses engaged high numbers of Ab-secreting cells, analysis of the many shared, somatically acquired mutations showed that the majority of the cells originated from a common virgin B cell. Kinetic considerations implied that an extremely selected population of hypermutated memory B cells must have existed in these individuals before the first systemic immunization with the Ag. A possible role for the mucosal immune system in the priming and selection of these cells is proposed.

Adult↗
PubMed1996

Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex.

Cytotoxic T cells recognize mosaic structures consisting of target peptides embedded within self-major histocompatibility complex (MHC) class I molecules. This structure has been described in great detail for several peptide-MHC complexes. In contrast, how T-cell receptors recognize peptide-MHC complexes have been less well characterized. We have used a complete set of singly substituted analogs of a mouse MHC class I, Kk-restricted peptide, influenza hemagglutinin (Ha)255-262, to address the binding specificity of this MHC molecule. Using the same peptide-MHC complexes we determined the fine specificity of two Ha255-262-specific, Kk-restricted T cells, and of a unique antibody, pSAN, specific for the same peptide-MHC complex. Independently, a model of the Ha255-262-Kk complex was generated through homology modeling and molecular mechanics refinement. The functional data and the model corroborated each other showing that peptide residues 1, 3, 4, 6, and 7 were exposed on the MHC surface and recognized by the T cells. Thus, the majority, and perhaps all, of the side chains of the non-primary anchor residues may be available for T-cell recognition, and contribute to the stringent specificity of T cells. A striking similarity between the specificity of the T cells and that of the pSAN antibody was found and most of the peptide residues, which could be recognized by the T cells, could also be recognized by the antibody.

Amino Acid Sequence↗
PubMed1996

Human thymic epithelial cells express functional HLA-DP molecules.

HLA-DP molecules function as restriction elements in the presentation of foreign antigens to T cells by antigen presenting cells and certain HLA-DP molecules confer susceptibility to autoimmune disease. Because HLA molecules play an essential role in thymic selection and elimination of autoreactive T lymphocytes, we examined whether human thymic epithelial cells (TEC) expressed HLA-DP molecules. We present evidence that TEC obtained from short time culture express low but significant levels of HLA-DP molecules. The expression of HLA-DP molecules was comparable to or higher than the expression of HLA-DQ but lower than that of HLA-DR. Upon IFN-gamma treatment, HLA-DP expression was strongly upregulated. Since HLA-DQ and DR expression was upregulated in parallel, the hierarchy between MHC class II isotypes remained unchanged following interferon treatment. TEC elicited significant proliferation of HLA-DP allospecific primed lymphocyte typing (PLT) CD4 T cell lines. IFN-gamma treatment strongly upregulated the HLA-DP allospecific PLT responses whereas other PLT responses remained largely unchanged. In conclusion, these data indicate that human thymus epithelial cells express significant levels of functional HLA-DP molecules.

Child, Preschool↗
PubMed1996

Apoptosis following interleukin-2 withdrawal from T cells: evidence for a regulatory role of CD18 (beta 2-integrin) molecules.

Following a successful immune response against invading microorganisms, the majority of activated T cells is eliminated, while a minor fraction survives as memory T cells. A decline in T lymphocyte growth factors such as interleukin-2 (IL-2) appears to play a role in the elimination of previously activated T cells. Thus, removal of IL-2 from proliferating T cells not only induces growth arrest, but triggers a massive cell death due to apoptosis. While the apoptotic response involves a series of well-described events, it remains less clear how apoptosis is regulated following IL-2 withdrawal. Here, we provide evidence that CD18 molecules (beta 2-integrins) play a regulatory role in the apoptotic response following removal of IL-2 from previously activated, antigen specific CD4+ T cell lines. Thus, CD18 mAb inhibited the apoptotic response to IL-2 deprivation, whereas mAb against other adhesion molecules (CD28, CD29, CD49d, CD80, CD86) did not. Secondly, IL-2 withdrawal resulted in a retarded apoptotic response in LFA-1 (CD11a/CD18) negative T cells obtained from a leukocyte adhesion deficiency (LAD) patient, as compared to LFA-1 positive T cell lines. Thirdly, co-culture of LFA-1 positive- and negative-T cells at different ratios induced apoptotic responses that were higher than expected, had the two lymphocyte populations not been interacting and significantly higher than that seen in pure LFA-1 negative T cells. Supernatants from LFA-1 positive T cell cultures undergoing apoptosis did not induce an enhanced apoptotic responses in LFA-1 negative T cells, and, reversely, culture supernatants from LFA-1 negative T cells did not rescue LFA-1 positive cells from undergoing apoptosis. The apoptotic response was partly blocked by IL-15, a newly identified T cell growth factor. Taken together, these findings suggest that CD18 molecules (beta 2-integrins) play a regulatory role in the apoptotic response following cytokine withdrawal, and that the regulation is mediated, at least partly, through T-T cell interactions. Thus, apoptotic death following IL-2 deprivation appears to be under "social" control by surrounding T cells.

Apoptosis↗
PubMed1996

Human thymic epithelial cells present superantigens to T-cell lines and thymocytes.

It is generally accepted that thymic epithelial cells (TEC) act as accessory cells in positive selection of pre-T cells. However, our knowledge of the antigen presentation and accessory cell function to human TEC is limited. Here we present results obtained by the use of serum-free cultured human TEC, showing that IFN-gamma-treated TEC are able to support T-cell-mediated responses to the bacterial superantigens (Sag) SEA and SEB, even at very low Sag concentrations. T-cell responses to TEC-presented Sags were dependent on the presence of the adhesion molecules ICAM-1, ICAM-2, LFA-1, and LFA-3, but not on CD4 and CD8 molecules. There is a low but significant expression of B7 molecules on human TEC, and treatment of TEC with anti-B7.1 and anti-B7.2 antibodies before Sag pulsing leads to decreased Sag responses, indicating a significant importance of B7 molecules on TEC. Both CD4+ T-cell lines and CD4+ as well as CD8+ subpopulations of thymocytes showed significant responses, whereas nonseparated thymocytes, CD4+8+, and CD4-CD8- thymocytes did not respond or showed very low responses. In conclusion, the present results demonstrate that cultured human TEC are able to present Sag to thymocytes.

Antibodies↗
PubMed1996

Immunodeficiency after allogeneic bone marrow transplantation in man: the role of antigen presenting cells.

We investigated the proliferative response of donor T cells to phytohemagglutinin (PHA) presented by donor non-T cells in 7 patients after allogeneic bone marrow transplantation. Compared with the cellular response in the healthy marrow donors, T cell proliferation was found to be deficient in every recipient, from 130 to 739 days after grafting. Results of cell mixing experiments showed that the non-T cells of the patients were as capable as healthy donor non-T cells in presenting PHA to normal donor T cells. However, T cells from patients did not proliferate after substituting donor non-T cells for non-T cells from patients. This inability of T cells to proliferate was most likely the result of ineffective interactions among T cell subsets in patients after allogeneic bone marrow transplantation.

Adolescent↗
PubMed1996

Cytotoxic T cell activity after HLA-mismatch bone marrow transplantation.

Six patients with various hematologic diseases were treated with HLA-haploidentical bone marrow mismatched for 1-2 loci at the disparate chromosome with a relative response in the mixed lymphocyte reaction (MLR) ranging between 0.04 and 0.96 (median 0.27). Thirty to 371 days after bone marrow grafting, patient lymphocytes (of donor origin) were tested for reactivity in mixed lymphocyte culture (MLC) and cell mediated lympholysis (CMLy) to lymphocytes from the host (cryopreserved before grafting), the marrow donor, and unrelated individuals. After grafting, Lymphocytes from the patients showed a host-specific decrease in proliferation and in cytotoxic response (%51Cr release in a standard chromium release assay), when compared to the pretransplant host-specific donor response, whereas the responses towards third party cells were unaffected. This host-specific unresponsiveness after HLA-mismatch bone marrow transplantation is compatible with a clonal deletion theory and might be the reason that this procedure is at all possible.

Adolescent↗
PubMed1995

Staphylococcal enterotoxins modulate interleukin 2 receptor expression and ligand-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription (Stat proteins).

Staphylococcal enterotoxins (SE) stimulate T cells expressing the appropriate variable region beta chain of (V beta) T-cell receptors and have been implicated in the pathogenesis of several autoimmune diseases. Depending on costimulatory signals, SE induce either proliferation or anergy in T cells. In addition, SE can induce an interleukin-2 (IL-2) nonresponsive state and apoptosis. Here, we show that SE induce dynamic changes in the expression of and signal transduction through the IL-2 receptor (IL-2R) beta and gamma chains (IL-2R beta and IL-2R gamma) in human antigen-specific CD4+ T-cell lines. Thus, after 4 hr of exposure to SEA and SEB, the expression of IL-2R beta was down-regulated, IL-2R gamma was slightly up-regulated, while IL-2R alpha remained largely unaffected. The changes in the composition of IL-2Rs were accompanied by inhibition of IL-2-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription called Stat3 and Stat5. In parallel experiments, IL-2-driven proliferation was inhibited significantly. After 16 hr of exposure to SE, the expression of IL-2R beta remained low, while that of IL2R alpha and IL2R gamma was further up-regulated, and ligand-induced tyrosine phosphorylation of Jak3 and Stat proteins was partly normalized. Yet, IL-2-driven proliferation remained profoundly inhibited, suggesting that signaling events other than Jak3/Stat activation had also been changed following SE stimulation. In conclusion, our data suggest that SE can modulate IL-2R expression and signal transduction involving the Jak/Stat pathway in CD4+ T-cell lines.

Apoptosis↗
PubMed1995

Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency.

A low plasma concentration of mannan-binding protein (MBP) impairs opsonisation and phagocytosis. Three different mutations in the MBP gene have a dominant effect on MBP concentration. We investigated the frequency of the abnormal MBP alleles in 228 unrelated patients suspected of various non-HIV-related immunodeficiencies. The frequency of heterozygotes for the abnormal alleles was not different from that in the background population (36.0% and 37.4%, respectively). By contrast, the frequency of homozygotes for the abnormal alleles was significantly increased (8.3% and 0.8%, respectively; p = 0.0017). This finding implies that homozygotes for abnormal MBP alleles are predisposed to recurrent infections.

Alleles↗
PubMed1995

Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein.

Mannan-binding protein (MBP) is a serum lectin participating in the innate immune defense by opsonizing various microorganisms for phagocytosis. Opsonization defect due to MBP deficiency and low levels of the protein can partially be explained by the dominant effect of three different mutations in the structural part of the MBP gene. Large interracial differences in the frequencies of these variants have previously been described, but they cannot explain the large interindividual variation in MBP serum concentration. We describe the existence of additional polymorphisms at positions -550 (H/L variants) and -221 (X/Y variants) in the promoter region of the gene. The promoter haplotypes, HY, LY, and LX, show associations with high, medium, and low levels of MBP serum concentrations, respectively. Moreover, this represents a genetic system with additive effect of haplotypes in which a low producing LX haplotype in the homozygous state down-regulates the basal expression of MBP as effectively as a single structural variant. Populations of pure Eskimos, Caucasoids, and black Africans show marked interethnic differences in the frequencies of promoter haplotypes regulating the expression of the normal peptide, with the HY haplotype frequency varying from 0.83 in Eskimos via 0.33 in Caucasoids to 0.08 in Africans. The LY haplotype frequency varies from 0.04 in Eskimos via 0.39 in Caucasoids to 0.23 in Africans. The LX haplotype frequency varies from 0.03 in Eskimos via 0.24 in Caucasoids to 0.23 in Africans. The effect of the promoter variants can explain almost all of the ethnic differences not explainable by the structural variants alone.

Base Sequence↗
PubMed1995

[Transplantation of lung lobe from a mother to a child previously transplanted with her bone marrow].

The lower lobe of the left lung was transplanted from a mother to her child, who previously had received a bone marrow transplant from the mother because of an immune defect. After the bone marrow transplant the child had developed progressive pulmonary fibrosis (obliterative bronchiolitis). The surgical procedure and the early postoperative period has been uncomplicated. Immunosuppression with corticosteroids was only given for a short period, after which no immunosuppressive treatment has been given. The operation and results for both donor and recipient are described. The early results are promising, but rehabilitation is progressing slowly.

Bone Marrow Transplantation↗
PubMed1995

Acute optic neuritis: myelin basic protein and proteolipid protein antibodies, affinity, and the HLA system.

Anti-myelin basic protein, anti-proteolipid protein, and anti-myelin basic protein peptide (amino acid residues 1-20, 63-88, and 89-101) antibody-secreting cells were studied in 20 patients with idiopathic optic neuritis, 20 with optic neuritis as part of multiple sclerosis, and 20 neurological control subjects. Antibody-secreting cells were enumerated with an immunospot assay; the relative binding affinity of the antibodies was estimated by elution with thiocyanate. Patients with optic neuritis had more anti-myelin basic protein and anti-proteolipid protein antibodies than did control subjects (both p < 0.05); there was no difference between idiopathic optic neuritis and optic neuritis as a symptom of multiple sclerosis. Presence of the multiple sclerosis-associated DRB1*1501 gene was not associated with preferential synthesis of high-affinity antibodies reactive with a single myelin basic protein peptide or with preferential synthesis of either anti-myelin basic protein or anti-proteolipid protein antibodies. The results demonstrate a potential for intrathecal synthesis of both anti-myelin basic protein and anti-proteolipid protein antibodies of high apparent affinity in patients with optic neuritis.

Adolescent↗
PubMed1995

Transplantation of a lobe of lung from mother to child following previous transplantation with maternal bone marrow.

A left lower lobe of the lung was transplanted from a mother to her child, who had previously received a maternal bone marrow transplant for an immune defect. Following the bone marrow transplantation, the child had developed severe pulmonary fibrosis. Surgery and the early postoperative course have been uncomplicated. Immunosuppression with corticosteroids was administered for a short period, after which all immunosuppressive treatment was discontinued. The operation and the outcome are described both in the donor and recipient. Rehabilitation was slow, but one year later the patient is doing well.

Adult↗