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Biomedical subjects

K Söderström

Publications and source records attributed to K Söderström.

At least 19 recordsLinked to original sources
PubMed2005

Characterisation of natural killer cells and CD56+ T-cells in sarcoidosis patients.

The aim of the current study was to investigate the frequency, phenotype and functional activity of natural killer (NK) cells and CD56+ T-cells in the bronchoalveolar lavage fluid and peripheral blood of patients with pulmonary sarcoidosis when compared with healthy volunteers, using staining with a panel of monoclonal antibodies followed by flow cytometry. The results revealed that the majority of the lung NK cell subpopulation expressed CD56(bright). In contrast, there was a predominant CD56(dim) subset in the blood of both patients and healthy controls. Most lung NK cells expressed C-type lectin-like human leukocyte antigen (HLA)-E-specific inhibitory receptor (i.e. CD94/NKG2A), but only a few lung NK cells expressed killer cell immunoglobulin-like inhibitory receptors specific for HLA-A, -B or -C molecules. In addition, a significantly increased number of CD56+ T-cells were observed in the blood of patients when compared with controls. Upon in vitro stimulation, both lung NK and CD56+ T-cells produced considerable amounts of interferon-gamma and tumour necrosis factor-alpha. Thus, in the lungs of patients with pulmonary sarcoidosis, a distinct phenotype of natural killer cells with the capacity to produce cytokines and actively participate in the T-helper 1-like inflammatory response associated with sarcoidosis was identified.

Adult↗
PubMed2002

Identification of the nonclassical HLA molecules, mica, as targets for humoral immunity associated with irreversible rejection of kidney allografts.

BACKGROUND: A substantial portion of kidney allografted patients experience early acute rejection episodes and even irreversible rejections in the early posttransplantation period. The presence of HLA alloantibodies before grafting is associated with early immunological complications, but in many patients rejections and graft loss occur even in the absence of such antibodies. METHODS: In this study, 748 serum samples taken before and at various time points after kidney transplantation from 139 patients were investigated for the presence, frequency, and specificity of kidney microvascular endothelial cell (KMEC)-reactive antibodies using major histocompatability class (MHC) I-related chain A (MICA) transfected cells and flow cytometry, antibody blocking experiments, and Western blotting. The ability of MICA-specific antibodies to fix complement and to induce a prothrombotic phenotype in KMECs was investigated. RESULTS: A polymorphic, 62 kDa nonclassical HLA class I molecule is identified as a new target molecule for reactivity in sera from patients with irreversible rejections. Specific blocking and transfection experiments verified the target molecule as MICA. A significant correlation was established for pre- or posttransplantation MICA humoral immunity and graft loss (P<0.001). MICA-specific antibody titers increased in the posttransplantation period and were present before any signs of clinical rejection. MICA antibody-containing patient sera induced a prothrombotic phenotype in KMECs. CONCLUSION: The increasing polymorphism detected at the MIC loci combined with the results of this study suggest that typing for the MIC loci and crossmatching for the detection of anti-MIC antibodies before transplantation should be used routinely. A better recipient-donor selection based on a negative crossmatch for both anti-donor HLA and MICA antibodies will decrease early graft rejections and losses.

Antibody Formation↗
PubMed2001

Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity.

Human CMV (HCMV) has evolved several strategies to evade the immune system of the infected host. Here, we investigated the role of the HCMV-encoded protein UL40 in the modulation of NK cell lysis. UL40 carries in its leader sequence a nonameric peptide similar to that found in many HLA class I molecules leader sequences. This peptide up-regulates the expression of HLA-E, the ligand for the NK cell inhibitory receptor CD94/NKG2A. The UL40-encoded HLA-E-binding peptide was present in all HCMV clinical (4636, 13B, 109B, 3C) and laboratory (AD169) strains analyzed. However, transfection of UL40 in different cell lines (293T, 721.221, K562) did not consistently confer protection from NK lysis (as measured using NKL and the newly generated NK line Nishi), despite a moderate up-regulation of HLA-E. Interestingly, combined transfection and treatment with IFN-gamma increased the inhibitory effect, via an HLA-E- and CD94/NKG2A-dependent mechanism. Although cells transfected with UL40 derived from either AD169 or 3C showed protection from NK cell lysis, infection of fibroblasts with the viruses resulted in a strong inhibition only with the clinical strain 3C. Our results suggest that UL40 and IFN-gamma-dependent up-regulation of HLA-E is only one possible mechanism to avoid NK cell recognition of HCMV infected cells.

Amino Acid Sequence↗
PubMed2001

Induction and abrogation of LACK reactive cells in the evolution of human leishmaniasis.

Peripheral blood mononuclear cells (PBMC) from cutaneous leishmaniasis patients with ongoing Leishmania aethiopica infection and individuals cured/under treatment from L. infantum or L. donovani infection were stimulated in vitro with LACK, the Leishmania homologue of receptors for activated C kinase. The LACK protein is conserved in related leishmanial species and is expressed both in the promastigote and amastigote stages of Leishmania. Our results show that LACK induced marked NK and some CD8+ cell proliferation in PBMC from cutaneous leishmaniasis patients with active disease. These responses were coupled with high levels of IFN-gamma and IL-10 production. At the concentration tested, the proliferative responses to freeze-thawed Leishmania antigen (Ft-Leish) were higher, while the levels of IFN-gamma were consistently lower than that of LACK. Although cells from individuals cured of leishmaniasis could respond to whole Leishmania lysate by proliferation and IFN-gamma production, there was no evident response to LACK. Ethiopian controls tested at the same time also showed LACK induced proliferation with IFN-gamma and IL-10 responses. Thus LACK reactivity in terms of proliferation and cytokine induction were present in cells from some healthy donors and most of the patients with active lesions, while this response was absent in individuals cured of L. infantum or L. donovani leishmaniasis. Since cure from leishmaniasis often results in life-long protection, and active but not cured patients showed in vitro responses to LACK stimulation, questions arose as to how this highly immunodominant molecule functions during human leishmanisasis. Some possible mechanisms are discussed.

Antigens, Protozoan↗
PubMed2000

Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts.

NK cells play a key role in the control of CMV infection in mice, but the mechanism by which NK cells can recognize and kill CMV-infected cells is unclear. In this study, the modulation of NK cell susceptibility of human CMV (hCMV)-infected cells was examined. We used a human lung and a human foreskin fibroblast cell line infected with clinical isolates (4636, 13B, or 109B) or with laboratory strains (AD169, Towne). The results indicate that all three hCMV clinical isolates confer a strong NK resistance, whereas only marginal or variable effects in the NK recognition were found when the laboratory strains were used. The same results were obtained regardless of the conditions of infection, effector cell activation status, cell culture conditions, and/or donor-target cell combinations. The NK cell inhibition did not correlate with HLA class I expression levels on the surface of the target cell and was independent of the leukocyte Ig-like receptor-1, as evaluated in Ab blocking experiments. No relevant changes were detected in the adhesion molecules ICAM-I and LFA-3 expressed on the cell surface of cells infected with hCMV clinical and laboratory strains. We conclude that hCMV possesses other mechanisms, related neither to target cell expression of HLA-I or adhesion molecules nor to NK cell expression of leukocyte Ig-like receptor-1, that confer resistance to NK cell recognition. Such mechanisms may be lost during in vitro passage of the virus. These results emphasize the differences between clinical hCMV isolates compared with laboratory strains.

Antigens, CD↗
PubMed1999

Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules.

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.

Animals↗
PubMed1998

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.

Animals↗
PubMed1997

CD94/NKG2 is the predominant inhibitory receptor involved in recognition of HLA-G by decidual and peripheral blood NK cells.

Prior studies demonstrated that NK cells isolated from adult peripheral blood kill the HLA-A-, HLA-B-, and HLA-C-deficient B lymphoblastoid cell line 721.221, but many are unable to kill 721.221 cells transfected with HLA-G, a molecule expressed preferentially on fetal cytotrophoblasts. To determine the biologic relevance of this recognition, we established NK cell clones from the placenta and demonstrate that these NK cells also were unable to kill 721.221 cells expressing HLA-G. Recognition of HLA-G by NK cells was prevented in the presence of anti-CD94 mAb, implicating CD94/NKG2 as the predominant inhibitory NK cell receptor for HLA-G used by decidual NK cells. In contrast, mAbs against the killer cell inhibitory receptors recognizing HLA-Cw3-related, HLA-Cw4-related, or HLA-Bw4 ligands did not affect NK cell killing of the HLA-G transfectants.

Adult↗
PubMed1996

Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory bowel diseases.

We have previously reported a preferential usage of V delta 1/V gamma 8 on TCR-gamma-delta-bearing intraepithelial lymphocytes of the normal human intestine as well as in the inflamed synovial tissue of patients with rheumatoid arthritis. The aim of the present study was to analyze V gene segment usage by gamma delta T cells of the intestine and peripheral blood (PB) from patients with inflammatory bowel disease. Freshly isolated lymphocytes were analyzed by flow cytometry using a panel of V gene subset-specific mAbs. The relative proportion of PB TCR-gamma delta+ cells was increased in patients with Crohn's disease as compared with controls. Interestingly, an increased proportion of PB gamma delta T cells of patients with ulcerative colitis or CrD expressed V delta and V gamma genes typically used by intraepithelial lymphocytes. Thus, increased proportions of V delta 1+ and V gamma 8+ cells were found in the PB of both patient groups. The majority of TCR-gamma delta+ intraepithelial lymphocytes (IEL) in inflamed and noninflamed intestine expressed V delta 1/V gamma 8, and a substantial proportion of V gamma(2,3,4)+ cells were found. These observations suggest a disease-associated appearance of "gut-like" gamma delta T cells in the periphery. Moreover, two patients had a large proportion of gamma delta T cells in their PB of which the majority expressed two distinct V gamma proteins. Both of these patients had a short duration of disease (1 and 10 mo, respectively) and the relative proportion of gamma delta T cells decreased in concert with stabilization of disease. Interestingly, one of the patients had a clonal expansion of a V gamma dual-expressing gamma delta T cell in the PB.

Base Sequence↗
PubMed1996

Selective modulation of collagen gene expression by different isoforms of platelet-derived growth factor in experimental wound healing.

Subcutaneous sponges in rat were used as a wound model to study the changes in collagen gene expression induced by different isoforms of platelet-derived growth factor (PDGF). The steady state levels of proalpha1(I) and proalpha1(III) collagens rose markedly in response to PDGF-AB treatment. In marked contrast to PDGF-AB, PDGF-BB exerted a down-regulatory effect on the expression of type I and III procollagen mRNA levels. In situ hybridisation signal for proalpha1(I) collagen mRNA was most prominent in the periphery of the sponges in response to PDGF-AB. In PDGF-AA and PDGF-BB treated sponges, however, the hybridisation signal for proalpha1(I) collagen mRNA was evenly distributed. Immunolabellings demonstrated the presence of type I and III collagen epitopes and thus revealed the deposition of these proteins into developing granulation tissue. The volume of ingrown granulation tissue was estimated by measuring the cross-sectional area of the samples. PDGF-AB and PDGF-BB were both effective resulting in a significant increase in the amount of granulation tissue. However, only a limited enhancement of granulation tissue ingrowth was observed in response to PDGF-AA treatment. To conclude, PDGF-AB and PDGF-BB induced significantly the ingrowth of repair tissue in wounds. PDGF-AB distinctively upregulated collagen gene expression, while PDGF-BB primarily seemed to be mitogenic.

Animals↗
PubMed1996

Induction of heat shock protein 60 expression in human monocytic cell lines infected with Mycobacterium leprae.

Monocytic cell lines (HL-60 and THP-1) were infected with viable Mycobacterium leprae. Levels of human hsp60 were estimated by Western blot (immunoblot) assay and a sandwich enzyme-linked immunosorbent assay. The results showed that infection of both of the cell lines induced the synthesis of human hsp60, which may be of significance in relation to autoimmune manifestations associated with mycobacterial infections.

Cell Line↗
PubMed1995

Analysis of gamma delta V region usage in normal and diseased human intestinal biopsies and peripheral blood by polymerase chain reaction (PCR) and flow cytometry.

The intestinal population of gamma delta T cell receptor (TCR)-bearing cells was characterized with regard to V delta and V gamma subtype expression. For this purpose, we utilized V gene-specific PCR of mRNA prepared from intestinal biopsies. Predominant expression of the V delta 1 subtype was demonstrated in the small intestine of patients with coeliac disease and in the inflamed colon of patients with inflammatory bowel diseases (IBD: ulcerative colitis and Crohn's disease) as well as in colon biopsies taken from macroscopically normal areas of colon. Although intestinal gamma delta T cells preferentially expressed V delta 1, other V delta transcripts could be detected, of which V delta 2 and V delta 5 were commonly expressed. Analysis of biopsies from mesenteric lymph nodes demonstrated a V delta repertoire similar to the mucosa. In peripheral blood on the other hand, high expression of both V delta 2 and V delta 1 was found. The predominant expression of V delta 1 transcripts in the intestinal mucosa of IBD patients correlated well with protein cell surface expression as analysed by flow cytometry using V delta 1- and V delta 2-specific antibodies. Selective expansion of gamma delta T cells could not be demonstrated within the inflamed mucosa as shown by mRNA analysis and flow cytometry. Instead, IBD patients demonstrated a decreased proportion of TCR gamma delta-carrying T cells in the inflamed mucosa compared with macroscopically normal area of colon. On the other hand, a significantly increased percentage of T cells bearing the gamma delta TCR was found in peripheral blood of patients with Crohn's disease compared with healthy individuals, indicating that local mucosal inflammation may influence the circulating gamma delta T cell population.

Base Sequence↗
PubMed1994

High expression of V gamma 8 is a shared feature of human gamma delta T cells in the epithelium of the gut and in the inflamed synovial tissue.

We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p < 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 < p < 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p < 0.002) and PB from RA patients (p < 0.02) as well as normal PB (p < 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.

Adult↗
PubMed1994

Inactivation of thrombin by a complex between rat mast-cell protease 1 and heparin proteoglycan.

Rat peritoneal mast cells were shown to inactivate thrombin rapidly. The thrombin-inactivating activity was purified to homogeneity by a combination of anion-exchange chromatography and h.p.l.c. on a Superdex 75 column. The purified thrombin inactivator had an apparent molecular mass of 29 kDa and an N-terminal amino acid sequence identical to rat mast-cell protease 1 (RMCP-1). After labelling of the mast cells in vivo with 35SO4(2-), RMCP-1 was recovered in a macromolecular complex with [35S]heparin proteoglycans. Dissociation of RMCP-1 from the heparin proteoglycans by Superdex 75 chromatography in the presence of 2 M NaCl resulted in a marked loss of the thrombin-inactivating activity displayed by the enzyme. When RMCP-1 was reconstituted with either endogenous [35S]heparin proteoglycans or standard pig mucosal heparin, the enzyme regained its thrombin-inactivating properties. Affinity chromatography of endogenous [35S]heparin on matrix-linked RMCP-1 demonstrated that all of the heparin molecules contained high-affinity binding sites for the mast-cell protease. In contrast, the endogenous mast-cell heparin showed low affinity for antithrombin, a protease inhibitor involved in the regulation of coagulation enzymes.

Amino Acid Sequence↗