Biomedical subjects

C Soderberg

Publications and source records attributed to C Soderberg.

18 recordsLinked to original sources

PubMed1996

CD13-specific autoimmunity in cytomegalovirus-infected immunocompromised patients.

Cytomegalovirus (CMV) infection has been suggested to be associated with various autoimmune manifestations, such as hemolytic anemia, granulocytopenia, and the formation of autoantibodies. Earlier we found that CMV is associated with a human protein, CD13 (aminopeptidase N), emanating from CMV-infected cells and serving an important function during CMV infection of susceptible cells. We hypothesized that CD13 might become immunogenic if presented to the immune system as a part of the CMV virion. The presence of CD13-specific antibodies was tested using a microcytotoxicity assay against CD13-positive human monocytes, or by flow cytometric assays against mouse cells transfected with human CD13; specificity was assessed by specific blocking with monoclonal antibodies. CD13 reactivity was also demonstrated in immunoprecipitation experiments. CD13-specific antibodies were identified in 15 of 33 bone marrow transplant patients, but exclusively in patients who had experienced either CMV disease (9/10) or CMV viremia (6/9), and appeared at the time of CMV detection. None of the remaining 14 patients without signs of CMV infection were positive for CD13 antibodies (P<0.0001). No antibody of this specificity was found in any of the control individuals (0/24), including patients with various autoimmune diseases, CMV-seropositive or -seronegative healthy individuals, and patients with acute EBV or HSV-1 infections. Thus, the CMV-associated autoantigen CD13 is immunogenic during CMV infection in bone marrow transplant patients. A specific response against autoantigens associated with infectious virus particles is suggested as a new and general mechanism to explain virus-induced autoimmune manifestations in man.

3T3 Cells↗

PubMed1996

Cytomegalovirus-induced CD13-specific autoimmunity--a possible cause of chronic graft-vs-host disease.

Cytomegalovirus (CMV) infection has been suggested to be associated with certain autoimmune phenomena as well as with the development of chronic graft-versus-host disease (cGVHD) following allogeneic bone marrow transplantation. Earlier we found that the CMV-associated host protein CD13 is immunogenic during CMV infection in allogeneic bone marrow transplant patients, resulting in production of CD13-specific antibodies (7). Here we found a close correlation between CD13-specific immunity and later development of cGVHD in 26 of 33 patients who could be evaluated for this disease. Of seven patients with CMV disease, six developed extensive cGVHD, all of whom had CD13 specific antibodies (P=0.0002). All 14 patients who were CD13-immune later developed either limited or extensive cGVHD (P=0.0008). Antibodies in sera from the CD13-immune patients suffering from cGVHD recognized normal structures in cryosectioned skin biopsies from control individuals, producing a staining pattern similar to that of CD13-specific monoclonal antibodies. The antibody binding could be specifically blocked by preincubation of the skin sections with a mixture of monoclonal antibodies against CD13, and was also abolished after preabsorption of sera to mouse cells expressing human CD13. No other common autoantibodies were identified in more than single patients. Furthermore, in vivo binding of IgM antibodies in a CD13-like fashion was preferentially demonstrated in skin and oral mucosa biopsies from the CD13-immune patients suffering from cGVHD. Thus, we suggest that CMV-induced CD13-specific autoimmunity contribute to tissue damage in chronic graft-versus-host reactions.

3T3 Cells↗

PubMed1996

Patient selection for hepatic resection of colorectal metastases.

OBJECTIVE: To determine the major factors governing patient outcome after hepatic resection of metastatic colorectal cancer and to formulate criteria for optimal resection. PATIENTS: We reviewed records of 74 patients (44 men, 30 women) who underwent resection of colorectal liver metastases. MAIN OUTCOME MEASURES: Sex, age, primary tumor location; Dukes tumor stage; disease-free interval after primary resection (synchronous vs metachronous); location, number, size, and distribution of liver metastases; operative complications; and mortality. RESULTS: The primary tumor location was rectosigmoid in 46 patients and the colon in the others. The tumor stage was Dukes A in one patient, Dukes B in 16, Dukes C in 31, and Dukes D (synchronous metastases) in 26. The disease-free interval was less than 12 months in 38 patients and 12 months or more in 36. The location of the metastases was the right lobe in 42 patients, left lobe in 22, and bilateral in seven. The cancer was unilobar in 55 patients and bilobar in 18. Surgical resection included wedge resection in 23 patients, segmentectomy in 30, lobectomy in seven, and trisegmentectomy in 12. The number of lesions resected was one in 50 patients, two or three in 18, and four or more in five. Nine patients had repeated liver resections because of recurrence. There were five postoperative deaths within 60 days (7%), four of which occurred after extended resection and were complicated by delayed liver failure and multisystem failure. An additional death occurred at 65 days after an apparently uneventful initial convalescence. Overall median survival was 35 months; actuarial 5- and 10-year survival rates were 24% and 12% respectively. There were significant relationships with survival (P<.05) for the number of metastases (three or fewer vs four or more), bilobar vs unilobar metastases, and extent of liver resection (wedge and segmental vs lobectomy and trisegmentectomy). A multiple logistic regression model (multivariate analysis) showed a significant correlation with survival (P<.05) for distribution of metastases (bilobar vs unilobar) and extent of resection (wedge and segmental vs lobectomy and trisegmentectomy). CONCLUSION: Patient selection for hepatic resection of colorectal cancer metastases based on standard clinical and tumor outcome variables should be expected to achieve long-term survival with low morbidity and mortality in bilobar disease or extended resection should generally be avoided, especially in medically compromised patients.

Aged↗

PubMed1996

CD45 isoforms on human CD4+ T-cell subsets.

We have examined the level of surface expression and functional properties of leukocyte function associated antigen-1, very late antigen-4, and CD45 isoforms on a panel of human CD4+ T-cell clones representative of TH0, TH1, and TH2 cells. There were no qualitative differences in the expression of these antigens among the three types of CD4+ T-cell clones. However, CD45RB was the only CD45 isoform that provided a costimulatory signal in a solid-phase antibody-induced cellular proliferation assay. Additionally, the antigen-induced proliferative response of T-cell clones was inhibited by soluble anti-CD45RO and anti-CD45RB antibodies. Our results suggest that CD45 isoforms differentially provide costimulatory signals to T cells. However, the ability of each CD45 isoform to provide a costimulatory signal does not differ among the TH0, TH1, or TH2 T-cell populations.

CD4-Positive T-Lymphocytes↗

PubMed1995

Modulation of the Grb2-associated protein complex in human CD4+ T cells by receptor activation.

A panel of human CD4+ T cell clones was utilized to dissect and analyze the biochemical consequences of activation of CD3 or CD28. To molecularly characterize receptor-activated proximal signaling events, tyrosine-phosphorylated proteins co-precipitating with a Grb2 fusion protein after receptor activation were analyzed. Ligation of CD28, but not other costimulatory molecules, induced the tyrosine phosphorylation of two previously identified Grb2 binding proteins (pp76 and pp116). A third Grb2 binding protein (pp36) was extensively tyrosine phosphophorylated in response to combined CD3 and CD28 activation, but not in response to ligation of either receptor alone. cAMP and co-ligation of CD45 affected the receptor-activated tyrosine phosphorylation of Grb2-associated proteins. Furthermore, we demonstrated that two signaling molecules, Vav and phosphatidylinositol 3'-kinase (PI(3)K), also interacted with the Grb2 protein complex. The activity of PI(3)K was required for T cell activation, because wortmannin, a PI(3)K inhibitor, blocked T cell proliferation and cytokine production induced by ligation of CD3 and CD28. In conclusion, we demonstrate that in activated human T cell clones, the composition of Grb2 protein complex is modulated by costimulatory signals and cAMP, which may be important for the regulation of intracellular signal transduction.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Costimulatory signals can selectively modulate cytokine production by subsets of CD4+ T cells.

Analysis of experimental animal models and human clinical samples has indicated that the selective activation of CD4+ T cell subsets with distinct profiles of cytokine production plays an important role in the pathogenesis of human inflammatory and allergic diseases. The possibility that differential activation of costimulatory pathways is a mechanism for selectively modulating cytokine production by CD4+ T cells was tested. The proliferative response and cytokines secreted by a panel of human CD4+ T cell clones, representative of Th1 or Th2/0 cells, in response to activation of different costimulatory pathways was measured. CD28-mediated costimulatory signals induced proliferation and IFN-gamma secretion by Th1 cells. Although CD28-ligation induced Th2/0 cells to proliferate, it did not trigger IL-4 production. Ligation of LFA-1 and CD45 isoforms also generated costimulatory signals activating cytokine secretion by the different types of T cell clones. Th1 cells secreted the same profile of cytokines, irrespective of which costimulatory pathway was engaged. However, the cytokine secreted by a subset of Th2/0 cells varied, depending upon which costimulatory pathways were activated. These results suggest that the costimulatory pathways activated by APCs can selectively influence cytokine production by CD4+ T cell subsets.

Animals↗

PubMed1995

Pathogen antigen- and superantigen-reactive synovial fluid T cells in reactive arthritis.

Analysis of pathogen-reactive T cell clones (CD3+4+8-TCR alpha beta +), isolated from the synovial fluid of 2 HLA-B27-positive patients with Yersinia enterocolitica-triggered reactive arthritis, has provided important information about the cellular immune response to this disease-inciting pathogen. This study demonstrates that the proteins secreted by Y. enterocolitica, including a protein with tyrosine phosphatase activity (YopH), are potent immunogens stimulating CD4+ cells within the inflamed joint. The pathogen-reactive T cell clones preferentially utilized a limited set of T cell receptor variable region gene segments. A purified Yersinia superantigen triggered a proliferative response in most of the antigen-reactive T cell clones tested. These results suggest that the activity of this pathogen's superantigen influences the cellular immune response to its antigens.

Adult↗

PubMed1994

Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered weekly on an outpatient basis with concurrent thoracic radiation to patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase I clinical trial, paclitaxel was administered as a 3-hour intravenous (IV) infusion, repeated every week for 6 weeks. The starting dose of paclitaxel was 10 mg/m2. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients if tolerated. Unacceptable toxicity was defined as grade 3 nonhematologic toxicity, excluding nausea and vomiting, and grade 4 hematologic toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Twenty-seven patients were entered onto this study through seven dose escalations (from 10 mg/m2/wk to 70 mg/m2/wk for 6 weeks). Severe esophagitis occurred at 70 mg/m2 (two patients with grade 4 disease and one patient with grade 2). One of six patients at 60 mg/m2 developed grade 3 esophagitis and three of seven patients had grade 2 esophagitis. One of 27 patients developed a hypersensitivity reaction. One of 27 patients developed grade 3 neutropenia. CONCLUSION: Esophagitis is the principle dose-limiting toxicity of weekly paclitaxel and thoracic radiation in the outpatient setting. A phase II trial using concurrent radiation and paclitaxel at the MTD of 60 mg/m2/wk is underway.

Adult↗

PubMed1993

Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease.

Forty-three CD3+4+8- TCR alpha beta+ Borrelia burgdorferi-reactive T cell clones isolated from the peripheral blood of a single patient with clinically active chronic Lyme arthritis were characterized. The spirochetal Ag recognized by 16 of these T cell clones was determined by reactivity with a panel of recombinant spirochetal Ag, which included the OspA, OspB, flagellin, Hsp60 and Hsp70 proteins. All three T cell clones reactive with heat shock proteins recognized a non-cross-reactive epitope unique to the spirochetal Ag. Analysis of the TCR V regions revealed preferential usage of V beta 5.1; 5 of 15 T cell clones that recognized an unidentified spirochetal Ag utilized this V beta gene segment. Most of the T cell clones recognized a given spirochetal Ag exclusively within the context of one HLA class II allele. However, two T cell clones, which recognized an unidentified Ag in the spirochetal lysate within the context of different HLA class II alleles, were both TCR V beta 5.1+, although each displayed a distinct alpha-chain. Moreover, in vitro incubation of this patient's PBMC with B. burgdorferi Ag resulted in a specific increase in the percentage of T cells expressing TCR V beta 5.1. These results indicate that B. burgdorferi has a V beta-selective factor influencing the cellular immune response in a patient with clinically active Lyme disease.

Adolescent↗

PubMed1992

Epitopes on the outer surface protein A of Borrelia burgdorferi recognized by antibodies and T cells of patients with Lyme disease.

We have characterized immunogenic epitopes of the 31-kDa outer surface protein A (OspA) protein of Borrelia burgdorferi, which is a major surface Ag of the spirochete causing Lyme disease. Full length and truncated forms of rOspA proteins were expressed in Escherichia coli, and their reactivities with antibodies and human T cell clones isolated from patients with Lyme disease were determined. The epitopes recognized by three of four OspA-reactive T cell clones are contained within the 60 COOH-terminal amino acids. Each of the four OspA-reactive T cell clones has a different HLA class II molecule involved in Ag recognition and recognizes a distinct epitope. One T cell clone promiscuously recognized an epitope in the context of different HLA-DQ molecules. In addition, the binding of a murine monoclonal anti-OspA antibody, as well as antibodies in sera of three of five patients with Lyme disease, was dependent upon the amino acids in the carboxy-terminal protion of this protein. Taken together, our results indicate that the 60 COOH-terminal amino acids of OspA contain epitopes recognized by human antibodies and T cells.

Antibodies, Bacterial↗

PubMed1992

Borrelia burgdorferi HSP70 homolog: characterization of an immunoreactive stress protein.

The gene encoding an immunoreactive Borrelia burgdorferi HSP70 homolog was isolated and characterized. The predicted amino acid sequence of this spirochetal protein confirms that this gene encodes a member of the HSP70 family of proteins. Although there appears to be a single copy of this gene on the spirochetal chromosome, two distinct transcripts hybridizing to the hsp70 probe are detected in RNA isolated from B. burgdorferi. The amount of spirochetal HSP70 RNA transcripts is shown to be thermally regulated. Antibodies in the serum of three Lyme arthritis patients and cloned T-cell lines isolated from one patient with Lyme arthritis recognize the expressed recombinant HSP70, indicating that it is an immunologically important spirochetal antigen. Antibodies in a rabbit antiserum, as well as antibodies in the serum of two of three Lyme arthritis patients examined, bound to expressed truncated recombinant HSP70s with 250 amino acids deleted from either the amino or carboxy terminus of the protein. However, antibodies in the serum of three Lyme arthritis patients, which were reactive with spirochetal HSP70, did not cross-react with human HSP70 proteins.

Adolescent↗

PubMed1991

Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis.

18 cloned T cell lines reactive with Borrelia burgdorferi proteins, all CD3+4+8-TCR-alpha/beta+ and restricted by HLA class II proteins, were isolated from four patients with chronic Lyme arthritis. Analysis of these T cell clones indicated that the T cell response to the Lyme disease spirochete is not oligoclonally restricted; yet all produced the same pattern of lymphokines, resembling that of murine type 1 T helper cells, after antigen-specific or nonspecific stimulation. Therefore, a subset of human CD4+ T cells, with a distinct profile of lymphokine secretion, is selectively activated by the pathogen inciting this chronic inflammatory disease.

Antigens, Bacterial↗

PubMed1991

T cell and antibody reactivity with the Borrelia burgdorferi 60-kDa heat shock protein in Lyme arthritis.

The reactivity of cloned T cells and serum antibodies, obtained from patients with chronic Lyme arthritis, with expressed recombinant B. burgdorferi 60-kDa heat shock protein homologue (HSP60) was analyzed. The expressed recombinant Borrelia burgdorferi HSP60 was bound by antibodies in the sera of patients with Lyme arthritis, but not by control sera. A T cell clone (CR253), isolated from one of four patients examined, exhibited an HLA-DR2 restricted proliferative response to the expressed recombinant B. burgdorferi HSP60. This T cell clone specifically recognized the HSP60 of B. burgdorferi and did not proliferate in response to the human, mycobacterial, or Escherichia coli HSP60 homologues. The epitope recognized by this cloned T cell, located between amino acids 260 and 274, is in a region of the spirochetal HSP60 that is not conserved between bacteria and eukaryotes.

Adolescent↗

PubMed1990

Plasma clearance and tissue distribution of recombinant human platelet-derived growth factor (B-chain homodimer) in rats.

125I-labeled human recombinant platelet-derived growth factor (B-chain homodimer; rHuPDGF-BB) was intravenously injected into male rats, and plasma clearance and tissue distribution of total and acid-insoluble radioactivity were determined. Insoluble radioactivity was rapidly cleared from plasma in a biphasic manner with estimated distribution and elimination half-lives of 5.2 and 68 min, respectively. Less than 10% of the injected radioactivity remained in plasma at 1 hr after injection. rHuPDGF-BB was widely distributed throughout body tissues. However, acid-insoluble radioactive concentrations greater than those in plasma were only observed in liver, kidneys, and spleen. The radioactive concentration of most tissues declined rapidly between 1 and 4 hr but increased in the intestinal contents. Radioactive concentrations decreased in all tissues and intestinal contents at 8 and 24 hr. Urine samples collected at the latter interval showed that 39% of the dose was excreted by the kidneys in an acid-soluble form. These results suggest that the rapid clearance of rHuPDGF-BB from plasma is the result of widespread tissue distribution, metabolism by the liver, and excretion by the kidneys. In this respect, the pharmacokinetic behavior of rHuPDGF-BB resembles that of other lymphokines and growth factors that have recently been studied.

Animals↗

PubMed1990

Analysis of T lymphocytes cloned from the synovial fluid and blood of a patient with Lyme arthritis.

Cloned T lymphocytes reactive with Borrelia burgdorferi proteins were isolated from a patient with chronic Lyme arthritis. All of the T cell clones which proliferated in response to Borrelia proteins were CD3 + CD4 + CD8 - TCR alpha beta + and HLA-DR restricted. One T cell clone (GN30) exhibited HLA-DR-restricted cytotoxic activity against antigen-presenting cells pulsed with Borrelia antigen. In response to Borrelia antigen, the T cell clones produced TNF-alpha, INF-gamma, and GM-CSF. There are at least three distinct spirochetal proteins recognized by the four T cell clones analyzed. Purified Borrelia proteins triggered the HLA-DR-restricted proliferative and cytotoxic responses, as well as lymphokine secretion by two of the T cell clones. The spirochetal protein which triggered the HLA-DR-restricted proliferative and cytotoxic activities of the T cell clone (GN30) isolated from synovial fluid is the 41 kd flagellar protein.

Antigens, Bacterial↗

PubMed1988

Analysis of murine lymphocyte subpopulations by dual-color flow cytometry: technical considerations and specificities of monoclonal antibodies directed against surface markers.

We performed detailed phenotypic analysis of murine lymphocytes from thymus, spleen, lymph node, and peripheral blood using commercially available monoclonal antibodies, each with specificities for membrane surface markers and dual-color flow cytometry. Erythrocyte lysis techniques were utilized for lymphocyte preparation so that inherent difficulties with gradient techniques would be avoided, such as the potential for loss of abnormally sized cells. These studies demonstrated that the specificities of each monoclonal must be carefully determined; for example, the Lyt-1 monoclonal, frequently utilized to identify helper/inducer T cells, also reacts with suppressor/cytotoxic (Lyt-2+) cells; helper/inducer cells are better studied with a more recently available monoclonal, L3T4. Cells from different tissues may differ greatly not only in the presence of surface markers, but also in the surface density of each marker; this density can be studied and quantitated using appropriate analytic software. We also show that larger and more granular lymphocytes appear to be enriched for surface Ia antigen, indicating that these cells may be activated or regulatory subsets; these large, Ia+ T-cells will be lost from analysis if standard, narrow gate settings are used for analyzing forward and side-scatter characteristics or for cell sorting.

Animals↗

PubMed1986

Effects of periodic positive airway pressure by mask on postoperative pulmonary function.

Postoperative pulmonary complications, alveolar-arteriolar oxygen difference ([A-a]O2-diff), peak expiratory flow (PEF) and forced vital capacity (FVC) were compared in patients using continuous positive airway pressure (CPAP) and positive expiratory pressure (PEP) administered by face mask against those of a control group using a deep-breathing device (Triflo). Forty-three consecutive, randomized patients undergoing elective upper abdominal surgery were included. CPAP, PEP and Triflo were administered for 30 consecutive breaths in every waking hour for three days postoperatively. The (A-a)O2-difference increased equally and significantly in the three groups after surgery, reaching a maximum on the first postoperative day. After this day, however, (A-a)O2-diff decreased in the CPAP and PEP groups, being significantly lower in the PEP group compared to the control group, two days postoperatively (p less than 0.05) and significantly lower in both the PEP and CPAP groups three days postoperatively (p less than 0.001 and p less than 0.05, respectively.) PEF did not differ significantly between the groups before or after surgery, while FVC was significantly higher in the PEP and CPAP groups, compared to control, on the third postoperative day (p less than 0.05). Atelectatic consolidation was observed in six of 15 patients in the control group three days postoperatively, the incidence being significantly lower in both the PEP group (0 of 15, p less than 0.001) and the CPAP group (one of 13, p less than 0.05). We concluded that periodic face mask administration of CPAP and PEP are superior to deep breathing exercises with respect to gas exchange, preservation of lung volumes and development of atelectasis after upper abdominal surgery. We also conclude that the simple and commercially available PEP mask is as effective as the more complicated CPAP system.

Abdomen↗

PubMedDate not supplied

Immune response modulation after burn injury: T cells and antibodies.

Studies have been conducted to characterize phenotypic and functional characteristics of murine and human cells after burn injury. The detailed analysis of T-cell distribution in the burned mouse, and the analysis of activation markers L3T4/Lyt-2 and Ia, reveals characteristic changes including the presence of "activated" suppressor cells during post-injury suppression. Studies of humoral markers suggest an increased production of IgG in burned animals upon sheep red blood cells (SRBC) challenge, accompanied by increased clearance or catabolism of serum antibody, which results in depressed serum levels. Finally, in vitro phagocytosis studies using fluorescein isothiocyanate (FITC)-labeled killed bacteria reveal that burn patient sera are clearly defective in their ability to promote opsonization of one or more specific organisms by neutrophils. The addition of exogenous IgG to the incubation medium improves this response, suggesting that postburn phagocytic depression is an opsonic defect, rather than an inhibitory effect of burn serum on neutrophils.

Animals↗