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Papers by kalle soderstrom

Research paper thumbnail of Induction and abrogation of LACK reactive cells in the evolution of human leishmaniasis

Clinical and Experimental Immunology, May 1, 2001

Peripheral blood mononuclear cells (PBMC) from cutaneous leishmaniasis patients with ongoing Leis... more 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-γ 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-γ were consistently lower than that of LACK. Although cells from individuals cured of leishmaniasis could respond to whole Leishmania lysate by proliferation and IFN-γ production, there was no evident response to LACK. Ethiopian controls tested at the same time also showed LACK induced proliferation with IFN-γ 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.

Research paper thumbnail of Selective modulation of Natural Killer (NK) cell phenotypes through chromatin modifying mechanisms

European Journal of Immunology, 2016

Natural killer (NK) cells are sentinels of the innate immune system by monitoring cell surfaces f... more Natural killer (NK) cells are sentinels of the innate immune system by monitoring cell surfaces for the expression of MHC class I molecules and stress markers. For example, NK cells are critical for immune defence against malignant or virus infected target cells by engaging activating receptors, such as NKp30, leading to a cytolytic response

Research paper thumbnail of 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

Journal of Immunology, Jun 15, 1994

We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a ne... more 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.

Research paper thumbnail of FRI0020 Blocking the inhibitory CD94/NKG2A NK cell receptor with a novel ANTI-NKG2A MAB enhances the susceptibility of rheumatoid arthritis fibroblast-like synoviocytes (FLS) to NK cell-mediated cytotoxicity

Annals of the Rheumatic Diseases, Jun 1, 2013

Conclusions: Our data indicate that mice deficient in mPGES-1 do not respond to vagus-mediated im... more Conclusions: Our data indicate that mice deficient in mPGES-1 do not respond to vagus-mediated immunosuppression. Moreover, we show immunosuppressant effects of PGE 2 on TNF release. These results implicate an involvement of PGE 2 as an important mediator in the cholinergic anti-inflammatory pathway, and provide support for further investigations regarding the interaction between cholinergic and prostaglandin systems.

Research paper thumbnail of Analysis of Cytokine Gene-Expression in Rheumatoid-Arthritis Using Quantitative Polymerase Chain-Reaction

Journal of Cellular Biochemistry, 1993

Research paper thumbnail of Quantitative Characterization by Mass Cytometry Reveals a Complex Immune Environment and Activation Pattern in the Peritoneal Fluid of Endometriosis Patients

Reproductive Sciences, 2018

Research paper thumbnail of The V-DELTA-2 and V-DELTA-2 T-Cell Receptor Repertoires in Synovial-Fluid and Peripheral-Blood of a Patient with Juvenile Rheumatoid-Arthritis

Arthritis & Rheumatism, 1992

Research paper thumbnail of Human γδT Cells that Inhibit the In Vitro Growth of the Asexual Blood Stages of the Plasmodium falciparum Parasite Express Cytolytic and Proinflammatory Molecules

Scandinavian Journal of Immunology, 1999

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential... more The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human γδ+ and αβ+ 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 γδ‐ and the αβT cells. Despite this fact, only γδT cells inhibited, both Vδ1+ and Vδ2+, 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 γδT‐cell target was the extracellular merozoite or schizont. The failure of αβT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the γ...

Research paper thumbnail of Characterization of NK Cells in Endometriosis Associated Pain

Reproductive Sciences, 2016

Research paper thumbnail of See Profile

Induction of human hsp60 expression in monocytic cell lines

Research paper thumbnail of AB0079 Synovial Explant Inflammatory Mediator Production is Correlated with Disease Activity in Rheumatoid Arthritis: A Cross Sectional Study

Annals of the Rheumatic Diseases, 2014

Methods: A549 cells were induced with IL-1b and treated with mPGES-1 inhibitor (compound III) or ... more Methods: A549 cells were induced with IL-1b and treated with mPGES-1 inhibitor (compound III) or COX-2 inhibitor (NS398). Eicosanoid profiles were analyzed using LC-MS/MS and protein profiles were analyzed using mass spectrometry based proteomics. FA composition of total lipids was determined using gas chromatography with flame ionization detector and sphingolipids were analysed by LC-MS/MS. Results: Prostanoid profiles in supernatants from the IL-1b-induced cells treated with the COX-2 or mPGES-1 inhibitors were significantly different suggesting diverse effects of the inhibitors on downstream pathways. Proteomic analysis of A549 cells identified the reduction of SCD levels in response to treatment with mPGES-1 or COX-2 inhibitors, as well as the suppression of the levels of a number of proteins involved in metabolism of fatty acids and sphingolipids. Conclusions: The results suggest that down-regulation of COX-2/mPGES-1/PGE2 axis affects the lipid metabolism in A549 cells. These effects have important implications regarding potential consequences of pharmacologic mPGES-1 inhibition.

Research paper thumbnail of OP0142 Masking CD94/NKG2A using a novel therapeutic MAB results in significant suppression of IL-6 levels and reduced osteoclast formation in rheumatoid arthritis ex vivo cultures

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background Natural killer (NK) cells expressing CD94/NKG2A, an inhibitory receptor bindi... more ABSTRACT Background Natural killer (NK) cells expressing CD94/NKG2A, an inhibitory receptor binding HLA-E, accumulate in the inflamed joints of Rheumatoid Arthritis (RA) patients [1]. At this site they frequently interact with multiple inflammatory cell subsets. Recent data indicate that NK cells may play a role in RA disease pathology by their capacity to trigger the differentiation of monocytes into osteoclasts [2]. Objectives The aim of this study was to determine whether blocking the CD94/NKG2A interactions with HLA-E using a novel therapeutic mAb affects osteoclastogenesis in ex vivo RA synovial fluid mononuclear cell (SFMC) cultures. Methods To study osteoclastogenesis and in vitro bone mineral erosion, SFMCs were cultured in the absence or presence of IL-15. These cultures were treated with and without the antagonistic humanized anti-NKG2A mAb (NNC141-0100) followed by analysis of the formation of TRAP+ multinucleated osteoclasts and functional bone mineral erosion. To measure cytokine release, supernatants were harvested at various time points followed by detection using a Bioplex array. Results Blocking CD94/NKG2A in SFMC cultures resulted in a significantly reduced formation of TRAP+ multinucleated cells (p<0.01, n=14), reduced bone mineral erosion (p<0.03, n=5), and reduced IL-6 levels (p<0.01, n=11). Conclusions This study shows that blocking CD94/NKG2A with anti-NKG2A mAb NNC141-0100 that is currently being developed for the treatment of RA, leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro. Based on these findings, we propose that anti-NKG2A therapy may have a beneficial effect in vivo in RA patients. Disclosure of Interest K. Söderström Employee of: novo nordisk, Y. Sundström Grant/Research support from: novo nordisk, L. Berg Grant/Research support from: novo nordisk, D. Schepis Grant/Research support from: novo nordisk, E. Galsgaard Shareholder of: novo nordisk, Employee of: novo nordisk, L. Klareskog Grant/Research support from: novo nordisk, N. Wagtmann Shareholder of: novo nordisk, Employee of: novo nordisk

Research paper thumbnail of FRI0021 Synovial Explant Activity is Associated with Disease Activity in Biologically Treated Rheumatoid Arthritis Patients: A Cohort Study

Annals of the Rheumatic Diseases, 2014

ACR20, 50 and 70 response, remission (rem; defined as Clinical Disease Activity Index [CDAI] ≤2.8... more ACR20, 50 and 70 response, remission (rem; defined as Clinical Disease Activity Index [CDAI] ≤2.8, Simplified Disease Activity Index [SDAI] ≤3.3, Boolean score ≤1), low disease activity (LDA; CDAI ≤10, SDAI ≤11) or improvement in physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI] >0.3) were assessed by disease duration and treatment subgroups. Results: 646 pts were randomized and treated with SC ABA (n=318) or ADA (n=328) on background MTX (71 and 70 pts with ≤6 months' disease duration; 247 and 258 pts with >6 months' disease duration). Baseline characteristics were balanced between the disease duration subgroups, with the exception of a higher percentage of males among pts with ≤6 months' disease duration treated with ADA compared with the other subgroups. Among pts with ≤6 months' disease duration, 23.9% (SC ABA) and 30.0% (ADA) of pts discontinued study treatment; 19.8% (SC ABA) and 24.0% (ADA) of pts with >6 months' disease duration discontinued. Clinical responses by disease duration at Years 1 (AMPLE primary endpoint) and 2 are summarized in the table. Conclusions: In contrast to what has been shown with DMARDs, data from this post hoc analysis of the AMPLE trial show that pts treated with effective biologic DMARDs (SC abatacept or adalimumab), whether treated early in the course of disease (≤6 months) or later, achieved comparable responses across a range of clinical measures.

Research paper thumbnail of OP0016 The Effects of Biologics on Imaging Pathology Reflects Changes in Ex Vivo Mediator Release from Rheumatoid Arthritis Synovial Explants: A Cohort Study

Annals of the Rheumatic Diseases, 2015

ABSTRACT

Research paper thumbnail of High expression of Vγ8 is a shared feature of human γδ T cells in the epithelium of the gut and in the inflamed synovial tissue

The Journal of Immunology

ABSTRACT

Research paper thumbnail of Analysis of TCRG and TCRD rearrangements using PCR and antibodies

Research paper thumbnail of Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory bowel diseases

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1996

We have previously reported a preferential usage of V delta 1/V gamma 8 on TCR-gamma-delta-bearin... more 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+ intraepith...

Research paper thumbnail of Synovial Cells Responding to a 65-kDa Mycobacterial Heat Shock Protein have a High Proportion of a TcRgammadelta Subtype Uncommon in Peripheral Blood

Scandinavian Journal of Immunology, 1990

We have analysed the ability of T cells from .synovial fluid mononuelear cells (SFMC) and from pe... more We have analysed the ability of T cells from .synovial fluid mononuelear cells (SFMC) and from peripheral blood mononuclear cells (PBMC) of inflammatory arthritic diseases to proliferate in response to mycobaclerial antigens (65-kDa heat shock protein [hspjof BCG, whole BCG) and lo ral collagen type II, The SFMC demonstrated a significantly greater ability to respond lo 65-kDa hsp of BCG, and lo whole BCG, compared with PBMC from the same patients. With collagen type II. only a small proportion ofthe patients showed a proliferative response, although with ihis antigen also SFMC responded better than PBMC\ There was no difference between SFMC and PBMC in the response to control antigen (tetanus toxoid), phytohaemagglutinin (PHA), or interleukin 2 (lL-2), A high proportion of cells in SFMC-derived shorl-term T-cell lines were of TcRj'fi type, often exceeding the number of TcRy/f type. There was a significantly higher proportion of TcRyi^ cells in ihe SFMC lines compared with the PBMC lines. ;md a large part of the TcRyi^ cells in the SFMC cullures was CDS ', The SFMC lines had a high proportion of (J-TCS-1 ' cells (V(ii) among their TcRyti cells, always exceeding the percentages of TiyA ' (Vy")) and BB3 ' (V^2). In the PBMC" lines, the distribution of TcR-;(5 sublypes was markedly differenl, with a TiyA'^/BB3"' population in the majority. These dala argue for a diflerent subpopulation distribution of TcRyiS cells in synovial fluid compared with pcripherai blood of patienls with inflammatory arthritic diseases,

Research paper thumbnail of Induction of human hsp60 expression in monocytic cell lines

International Immunology, 1992

Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 ... more Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells.

Research paper thumbnail of Role of hsp60 during Autoimmune and Bacterial Inflammation

Immunological Reviews, 1991

Heat-shock proteins (hsp) are a group of proteins with a highly conserved structure in evolution,... more Heat-shock proteins (hsp) are a group of proteins with a highly conserved structure in evolution, which originally attracted the interest of molecular biologists studying gene regulation, but now are challenging also for the immunologist with a number of fundamental questions in relation to infection and autoimmunity. The immunogenicity of several hsp constituents of bacteria and parasites for the host T-cell system makes them of central interest for those who are trying to manipulate the protective immune responses against microorganisms. The hsp60 protein, originally characterized in E. coli as the groEL protein, and subsequently shown to have homologues in several other species, including humans (Jindal et al. 1989), is probably among the most studied in this regard, partly because recombinant myeobacterial hsp60 was made easily available for experimental immunologists. An almost bewildering number of observations suggest that T cells specific for hsp60 are involved in phenomena ranging from organ-specific inflammatory diseases like arthritis (van Eden et al. 1988) or diabetes (Elias et al. 1990) to tolerance induction (van den Broek et al. 1989), suggesting that many of the T cells recognizing bacterial hsp60 also crossreact with endogenous hsp60. Starting with our original interests in T-cell responsiveness against mycobacteria and local immunity in arthritis, respectively, we considered that at least two basic questions needed to be addressed from the findings related above; one question being when, where and how mammalian hsp60 is expressed; particularly, when do the determinants of this protein become available for recognition by immune cells?

Research paper thumbnail of Induction and abrogation of LACK reactive cells in the evolution of human leishmaniasis

Clinical and Experimental Immunology, May 1, 2001

Peripheral blood mononuclear cells (PBMC) from cutaneous leishmaniasis patients with ongoing Leis... more 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-γ 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-γ were consistently lower than that of LACK. Although cells from individuals cured of leishmaniasis could respond to whole Leishmania lysate by proliferation and IFN-γ production, there was no evident response to LACK. Ethiopian controls tested at the same time also showed LACK induced proliferation with IFN-γ 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.

Research paper thumbnail of Selective modulation of Natural Killer (NK) cell phenotypes through chromatin modifying mechanisms

European Journal of Immunology, 2016

Natural killer (NK) cells are sentinels of the innate immune system by monitoring cell surfaces f... more Natural killer (NK) cells are sentinels of the innate immune system by monitoring cell surfaces for the expression of MHC class I molecules and stress markers. For example, NK cells are critical for immune defence against malignant or virus infected target cells by engaging activating receptors, such as NKp30, leading to a cytolytic response

Research paper thumbnail of 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

Journal of Immunology, Jun 15, 1994

We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a ne... more 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.

Research paper thumbnail of FRI0020 Blocking the inhibitory CD94/NKG2A NK cell receptor with a novel ANTI-NKG2A MAB enhances the susceptibility of rheumatoid arthritis fibroblast-like synoviocytes (FLS) to NK cell-mediated cytotoxicity

Annals of the Rheumatic Diseases, Jun 1, 2013

Conclusions: Our data indicate that mice deficient in mPGES-1 do not respond to vagus-mediated im... more Conclusions: Our data indicate that mice deficient in mPGES-1 do not respond to vagus-mediated immunosuppression. Moreover, we show immunosuppressant effects of PGE 2 on TNF release. These results implicate an involvement of PGE 2 as an important mediator in the cholinergic anti-inflammatory pathway, and provide support for further investigations regarding the interaction between cholinergic and prostaglandin systems.

Research paper thumbnail of Analysis of Cytokine Gene-Expression in Rheumatoid-Arthritis Using Quantitative Polymerase Chain-Reaction

Journal of Cellular Biochemistry, 1993

Research paper thumbnail of Quantitative Characterization by Mass Cytometry Reveals a Complex Immune Environment and Activation Pattern in the Peritoneal Fluid of Endometriosis Patients

Reproductive Sciences, 2018

Research paper thumbnail of The V-DELTA-2 and V-DELTA-2 T-Cell Receptor Repertoires in Synovial-Fluid and Peripheral-Blood of a Patient with Juvenile Rheumatoid-Arthritis

Arthritis & Rheumatism, 1992

Research paper thumbnail of Human γδT Cells that Inhibit the In Vitro Growth of the Asexual Blood Stages of the Plasmodium falciparum Parasite Express Cytolytic and Proinflammatory Molecules

Scandinavian Journal of Immunology, 1999

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential... more The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human γδ+ and αβ+ 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 γδ‐ and the αβT cells. Despite this fact, only γδT cells inhibited, both Vδ1+ and Vδ2+, 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 γδT‐cell target was the extracellular merozoite or schizont. The failure of αβT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the γ...

Research paper thumbnail of Characterization of NK Cells in Endometriosis Associated Pain

Reproductive Sciences, 2016

Research paper thumbnail of See Profile

Induction of human hsp60 expression in monocytic cell lines

Research paper thumbnail of AB0079 Synovial Explant Inflammatory Mediator Production is Correlated with Disease Activity in Rheumatoid Arthritis: A Cross Sectional Study

Annals of the Rheumatic Diseases, 2014

Methods: A549 cells were induced with IL-1b and treated with mPGES-1 inhibitor (compound III) or ... more Methods: A549 cells were induced with IL-1b and treated with mPGES-1 inhibitor (compound III) or COX-2 inhibitor (NS398). Eicosanoid profiles were analyzed using LC-MS/MS and protein profiles were analyzed using mass spectrometry based proteomics. FA composition of total lipids was determined using gas chromatography with flame ionization detector and sphingolipids were analysed by LC-MS/MS. Results: Prostanoid profiles in supernatants from the IL-1b-induced cells treated with the COX-2 or mPGES-1 inhibitors were significantly different suggesting diverse effects of the inhibitors on downstream pathways. Proteomic analysis of A549 cells identified the reduction of SCD levels in response to treatment with mPGES-1 or COX-2 inhibitors, as well as the suppression of the levels of a number of proteins involved in metabolism of fatty acids and sphingolipids. Conclusions: The results suggest that down-regulation of COX-2/mPGES-1/PGE2 axis affects the lipid metabolism in A549 cells. These effects have important implications regarding potential consequences of pharmacologic mPGES-1 inhibition.

Research paper thumbnail of OP0142 Masking CD94/NKG2A using a novel therapeutic MAB results in significant suppression of IL-6 levels and reduced osteoclast formation in rheumatoid arthritis ex vivo cultures

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background Natural killer (NK) cells expressing CD94/NKG2A, an inhibitory receptor bindi... more ABSTRACT Background Natural killer (NK) cells expressing CD94/NKG2A, an inhibitory receptor binding HLA-E, accumulate in the inflamed joints of Rheumatoid Arthritis (RA) patients [1]. At this site they frequently interact with multiple inflammatory cell subsets. Recent data indicate that NK cells may play a role in RA disease pathology by their capacity to trigger the differentiation of monocytes into osteoclasts [2]. Objectives The aim of this study was to determine whether blocking the CD94/NKG2A interactions with HLA-E using a novel therapeutic mAb affects osteoclastogenesis in ex vivo RA synovial fluid mononuclear cell (SFMC) cultures. Methods To study osteoclastogenesis and in vitro bone mineral erosion, SFMCs were cultured in the absence or presence of IL-15. These cultures were treated with and without the antagonistic humanized anti-NKG2A mAb (NNC141-0100) followed by analysis of the formation of TRAP+ multinucleated osteoclasts and functional bone mineral erosion. To measure cytokine release, supernatants were harvested at various time points followed by detection using a Bioplex array. Results Blocking CD94/NKG2A in SFMC cultures resulted in a significantly reduced formation of TRAP+ multinucleated cells (p<0.01, n=14), reduced bone mineral erosion (p<0.03, n=5), and reduced IL-6 levels (p<0.01, n=11). Conclusions This study shows that blocking CD94/NKG2A with anti-NKG2A mAb NNC141-0100 that is currently being developed for the treatment of RA, leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro. Based on these findings, we propose that anti-NKG2A therapy may have a beneficial effect in vivo in RA patients. Disclosure of Interest K. Söderström Employee of: novo nordisk, Y. Sundström Grant/Research support from: novo nordisk, L. Berg Grant/Research support from: novo nordisk, D. Schepis Grant/Research support from: novo nordisk, E. Galsgaard Shareholder of: novo nordisk, Employee of: novo nordisk, L. Klareskog Grant/Research support from: novo nordisk, N. Wagtmann Shareholder of: novo nordisk, Employee of: novo nordisk

Research paper thumbnail of FRI0021 Synovial Explant Activity is Associated with Disease Activity in Biologically Treated Rheumatoid Arthritis Patients: A Cohort Study

Annals of the Rheumatic Diseases, 2014

ACR20, 50 and 70 response, remission (rem; defined as Clinical Disease Activity Index [CDAI] ≤2.8... more ACR20, 50 and 70 response, remission (rem; defined as Clinical Disease Activity Index [CDAI] ≤2.8, Simplified Disease Activity Index [SDAI] ≤3.3, Boolean score ≤1), low disease activity (LDA; CDAI ≤10, SDAI ≤11) or improvement in physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI] >0.3) were assessed by disease duration and treatment subgroups. Results: 646 pts were randomized and treated with SC ABA (n=318) or ADA (n=328) on background MTX (71 and 70 pts with ≤6 months' disease duration; 247 and 258 pts with >6 months' disease duration). Baseline characteristics were balanced between the disease duration subgroups, with the exception of a higher percentage of males among pts with ≤6 months' disease duration treated with ADA compared with the other subgroups. Among pts with ≤6 months' disease duration, 23.9% (SC ABA) and 30.0% (ADA) of pts discontinued study treatment; 19.8% (SC ABA) and 24.0% (ADA) of pts with >6 months' disease duration discontinued. Clinical responses by disease duration at Years 1 (AMPLE primary endpoint) and 2 are summarized in the table. Conclusions: In contrast to what has been shown with DMARDs, data from this post hoc analysis of the AMPLE trial show that pts treated with effective biologic DMARDs (SC abatacept or adalimumab), whether treated early in the course of disease (≤6 months) or later, achieved comparable responses across a range of clinical measures.

Research paper thumbnail of OP0016 The Effects of Biologics on Imaging Pathology Reflects Changes in Ex Vivo Mediator Release from Rheumatoid Arthritis Synovial Explants: A Cohort Study

Annals of the Rheumatic Diseases, 2015

ABSTRACT

Research paper thumbnail of High expression of Vγ8 is a shared feature of human γδ T cells in the epithelium of the gut and in the inflamed synovial tissue

The Journal of Immunology

ABSTRACT

Research paper thumbnail of Analysis of TCRG and TCRD rearrangements using PCR and antibodies

Research paper thumbnail of Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory bowel diseases

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1996

We have previously reported a preferential usage of V delta 1/V gamma 8 on TCR-gamma-delta-bearin... more 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+ intraepith...

Research paper thumbnail of Synovial Cells Responding to a 65-kDa Mycobacterial Heat Shock Protein have a High Proportion of a TcRgammadelta Subtype Uncommon in Peripheral Blood

Scandinavian Journal of Immunology, 1990

We have analysed the ability of T cells from .synovial fluid mononuelear cells (SFMC) and from pe... more We have analysed the ability of T cells from .synovial fluid mononuelear cells (SFMC) and from peripheral blood mononuclear cells (PBMC) of inflammatory arthritic diseases to proliferate in response to mycobaclerial antigens (65-kDa heat shock protein [hspjof BCG, whole BCG) and lo ral collagen type II, The SFMC demonstrated a significantly greater ability to respond lo 65-kDa hsp of BCG, and lo whole BCG, compared with PBMC from the same patients. With collagen type II. only a small proportion ofthe patients showed a proliferative response, although with ihis antigen also SFMC responded better than PBMC\ There was no difference between SFMC and PBMC in the response to control antigen (tetanus toxoid), phytohaemagglutinin (PHA), or interleukin 2 (lL-2), A high proportion of cells in SFMC-derived shorl-term T-cell lines were of TcRj'fi type, often exceeding the number of TcRy/f type. There was a significantly higher proportion of TcRyi^ cells in ihe SFMC lines compared with the PBMC lines. ;md a large part of the TcRyi^ cells in the SFMC cullures was CDS ', The SFMC lines had a high proportion of (J-TCS-1 ' cells (V(ii) among their TcRyti cells, always exceeding the percentages of TiyA ' (Vy")) and BB3 ' (V^2). In the PBMC" lines, the distribution of TcR-;(5 sublypes was markedly differenl, with a TiyA'^/BB3"' population in the majority. These dala argue for a diflerent subpopulation distribution of TcRyiS cells in synovial fluid compared with pcripherai blood of patienls with inflammatory arthritic diseases,

Research paper thumbnail of Induction of human hsp60 expression in monocytic cell lines

International Immunology, 1992

Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 ... more Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells.

Research paper thumbnail of Role of hsp60 during Autoimmune and Bacterial Inflammation

Immunological Reviews, 1991

Heat-shock proteins (hsp) are a group of proteins with a highly conserved structure in evolution,... more Heat-shock proteins (hsp) are a group of proteins with a highly conserved structure in evolution, which originally attracted the interest of molecular biologists studying gene regulation, but now are challenging also for the immunologist with a number of fundamental questions in relation to infection and autoimmunity. The immunogenicity of several hsp constituents of bacteria and parasites for the host T-cell system makes them of central interest for those who are trying to manipulate the protective immune responses against microorganisms. The hsp60 protein, originally characterized in E. coli as the groEL protein, and subsequently shown to have homologues in several other species, including humans (Jindal et al. 1989), is probably among the most studied in this regard, partly because recombinant myeobacterial hsp60 was made easily available for experimental immunologists. An almost bewildering number of observations suggest that T cells specific for hsp60 are involved in phenomena ranging from organ-specific inflammatory diseases like arthritis (van Eden et al. 1988) or diabetes (Elias et al. 1990) to tolerance induction (van den Broek et al. 1989), suggesting that many of the T cells recognizing bacterial hsp60 also crossreact with endogenous hsp60. Starting with our original interests in T-cell responsiveness against mycobacteria and local immunity in arthritis, respectively, we considered that at least two basic questions needed to be addressed from the findings related above; one question being when, where and how mammalian hsp60 is expressed; particularly, when do the determinants of this protein become available for recognition by immune cells?