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Biomedical subjects

I J ten Berge

Publications and source records attributed to I J ten Berge.

At least 19 recordsLinked to original sources
PubMed2001

Differentiation of cytomegalovirus-specific CD8(+) T cells in healthy and immunosuppressed virus carriers.

During immunosuppression, cytomegalovirus (CMV) can reactivate and cause serious clinical problems. Normally, abundant virus replication is suppressed by immune effector mechanisms. To study the interaction between CD8(+) T cells and persisting viruses, frequencies and phenotypes of CMV-specific CD8(+) T cells were determined in healthy individuals and compared to those in renal transplant recipients. In healthy donors, function of circulating virus-specific CD8(+) T cells, as measured by peptide-induced interferon gamma (IFN-gamma) production, but not the number of virus-specific T cells enumerated by binding of specific tetrameric peptide/HLA complexes, correlated with the number of CMV-specific IFN-gamma-secreting CD4(+) helper T cells. Circulating CMV- specific CD8(+) T cells did not express CCR7 and may therefore not be able to recirculate through peripheral lymph nodes. Based on coexpression of CD27 and CD45R0 most CMV-specific T cells in healthy donors appeared to be memory-type cells. Remarkably, frequencies of CMV-specific CD8(+) T cells were significantly higher in immunosuppressed individuals than in healthy donors. In these patients CMV-specific cells predominantly had an effector phenotype, that is, CD45R0(+)CD27(-)CCR7(-) or CD45RA(+)CD27(-)CCR7(-) and contained both granzyme B and perforin. Our data show that in response to immunosuppressive medication quantitative and qualitative changes occur in the CD8(+) T-cell compartment. These adaptations may be instrumental to maintain CMV latency. (Blood. 2001;98:754-761)

Adult↗
PubMed2001

Rejection of a kidney transplant does not always lead to priming of cytotoxic T cells against mismatched donor HLA class I antigens.

BACKGROUND: Previous studies showed that graft rejection is often associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor cells. Similar high avidity CTLs have been found in individuals who have formed IgG anti-HLA antibodies. The presence of such CTLs to a specific HLA mismatch is therefore considered to be a reflection of an activated immune system, and a contraindication for retransplantation with a donor sharing this particular HLA class I mismatch. METHODS: In our study we investigated whether patients have always primed CTLs against all individual HLA class I mismatches present on a rejected graft. Therefore, 14 patients who had undergone transplantectomy after irreversible kidney graft rejection were analyzed with respect to donor-specific CTLp frequencies and the presence or absence of high avidity CTLs directed against HLA class I mismatches present on the rejected graft. RESULTS: Patients, who have not formed anti-HLA antibodies against the donor have mainly naive CTLs. Most of the patients, that have developed IgG anti-HLA antibodies against a donor mismatch, have primed CTLs directed against that particular mismatch. However, patients with IgM anti-HLA antibodies only, and patients with IgG anti-HLA antibodies in historical sera but no IgG anti-HLA antibodies in current sera, have mainly naive CTLs against the donor HLA mismatch. CONCLUSION: Our results suggest that it is not always necessary to exclude repeated HLA class I mismatches for a subsequent transplantation. In addition to good anti-HLA antibody screening, the CTLp-assay may be a useful tool for donor-selection in retransplant candidates.

Antibodies↗
PubMed2001

Non FcR-binding murine antihuman CD3 monoclonal antibody is capable of productive TCR signalling and induces proliferation in the presence of costimulation.

CLB T3/4.A is a non FcR-binding CD3 mAb of the murine IgA isotype, which may be used as an alternative for the mitogenic OKT3 mAb in the treatment of acute cellular rejection after organ transplantation. We studied TCR signalling and T cell activation in response to T3/4.A in normal human PBMC in vitro. T3/4.A induced a rapid rise in free cytoplasmic Ca(2+), not different from the response to mitogenic CD3 mAb. However, protein tyrosine phosphorylation and, particularly, MAPK activation, were reduced as compared to mitogenic CD3 mAb. T3/4.A enhanced expression of both CD69 and CD25, but proliferation and detectable cytokine production did not occur. Addition of either CD28 mAb or IL-2 induced a strong proliferative response, which was accompanied by cytokine production. At higher mAb concentrations, T cell activation decreased, which correlated with TCR downmodulation. To exclude the possibility that activation by T3/4.A depends on interaction of murine IgA Fc with as yet unknown FcR, we showed that also with CD3 mAb F(ab')2 fragments upregulation of activation molecules occurred, as well as proliferation in the presence of costimulation. We conclude that the non FcR-binding murine IgA mAb T3/4.A acts as a partial agonist and leads to proliferation and cytokine production only in the presence of appropriate costimuli. These findings may explain the mitigated cytokine release syndrome observed in vivo with some nonmitogenic CD3 mAbs.

Animals↗
PubMed2001

Interferon-gamma administration after abdominal surgery rescues antigen-specific helper T cell immune reactivity.

Antigen-induced activation of T cells is determined by many factors. Among these factors are (i) the number of T-cell receptors (TCRs) triggered by TCR ligands on antigen-presenting cells (APCs), and (ii) the intrinsic cellular threshold for activation. T-cell receptor triggering is optimized by adhesion molecules that form the interaction site between T cells and APCs, i.e. the immunological synapse. In addition, signals through co-stimulatory molecules lower the intrinsic T-cell activation threshold. Immunosuppressive agents and traumatic events such as major operative procedures change physiological T-cell responses. Depressed immune functions after surgery are presumed to render patients more susceptible to pathogens. Interferon-gamma (IFNgamma) is a type II homodimeric cytokine with multiple immunostimulatory properties. Several studies have been performed to assess the effects of IFNgamma treatment in patients in need of increased immune reactivity. However, until now, the effect of IFNgamma on human antigen specific CD4(pos) T-cell reactivity after surgically-induced immunosuppression has not been reported. Therefore, a comparative trial of recombinant human (rh) IFNgamma versus placebo in patients after abdominal surgery was initiated. Antigen-specific helper T cell immune reactivity was assessed by antigen-induced cytokine production, intracellular cytokine staining and flow cytometry. A single dose of rhIFNgamma rescued down-modulation of antigen-specific CD4(pos) T-cell reactivity, concomitant with an up-regulation of TCR-ligands on antigen-presenting cells. Selected patients may benefit from the immunostimulatory properties of rhIFNgamma administration in vivo.

Abdomen↗
PubMed2001

Interferon-gamma in healthy subjects: selective modulation of inflammatory mediators.

BACKGROUND: It is suggested that interferon-gamma (IFN-gamma), like other cytokines, is a mediator in the host inflammatory response, which could be of importance in the pathophysiology of sepsis. The role of IFN-gamma in human host inflammatory responses, however, has not been studied. DESIGN: In a placebo-controlled trial we studied the acute effects of IFN-gamma administration on host inflammatory mediators in healthy men: i.e. the cytokine/chemokine cascade system, acute-phase proteins, activation markers of the innate cellular immunity and coagulation/fibrinolysis parameters. RESULTS: IFN-gamma increased plasma levels of interleukin-6 (IL-6), IL-8 and IFN-gamma-inducible protein-10 (IP-10) (P < 0.05), but did not affect plasma levels of other cytokines (IL-4, IL-10, tumour necrosis factor-alpha, IL-12p40/p70). Plasma concentrations of C-reactive protein and secretory phospholipase A2 both increased (P < 0.05). Plasma levels of the leucocyte activation marker elastase-alpha1-antitrypsin complexes increased after IFN-gamma administration (P < 0.05), IFN-gamma increased the percentage of high-affinity Fcgamma-receptor (FcgammaRI) -positive neutrophils (P < 0.05), but did not affect the mean fluorescence intensity of FcgammaRI on neutrophils. Procoagulant and profibrinolytic effects of IFN-gamma were evidenced by increased plasma levels of prothrombin fragment F1 + F2, tissue-plasminogen activator and plasmin-alpha2-antiplasmin complexes (P < 0.05). CONCLUSION: We conclude that IFN-gamma selectively affects host inflammatory mediators in humans.

Acute-Phase Proteins↗
PubMed2000

A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans.

Thalidomide is increasingly being used as adjuvant therapy for patients with mycobacterial and human immunodeficiency virus (HIV) infections. The T-helper (Th)1 cytokine-Th2 cytokine balance critically determines the outcomes of these diseases. To obtain insight into the effect of thalidomide on the capacity of lymphocytes to produce Th1 and Th2 cytokines, six healthy volunteers received an oral dose (400 mg) of thalidomide. Before and at 3, 6, and 24 h after ingestion of thalidomide, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for 24 h with the T-cell stimulant staphylococcal enterotoxin B (SEB) or anti-CD3/CD28. In all six volunteers ingestion of thalidomide was associated with enhanced SEB- and anti-CD3/CD28-induced production of the Th1 cytokine gamma interferon (P < 0.05) and a decrease in the level of anti-CD3/CD28-induced interleukin-5 (IL-5) production (P < 0.05). The levels of IL-2 (Th1) and IL-4 (Th2) released remained unchanged. These changes were accompanied by an increase in the amount of IL-12p40 released by the PBMCs 6 h after ingestion of thalidomide (P < 0.05). Thus, a single oral dose of thalidomide causes a Th1-type response in healthy humans. This finding offers a potential explanation for the positive effect of thalidomide in patients with mycobacterial and HIV infections.

Adult↗
PubMed2000

Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection.

Although virus-specific CD4(+) T cells have been characterized extensively in latently infected individuals, it is unclear how these protective T-cell responses develop during primary virus infection in humans. Here, we analyzed the kinetics and characteristics of cytomegalovirus-specific (CMV-specific) CD4(+) T cells in the course of primary CMV infection in kidney transplant recipients. Our data reveal that, as the first sign of specific immunity, circulating CMV-specific CD4(+) T cells become detectable with a median of 7 days after first appearance of CMV-DNA in peripheral blood. These cells produce the T helper 1 type (Th1) cytokines IFNgamma and TNFalpha, but not the T helper 2 type (Th2) cytokine IL4. In primary CMV infection, the vast majority of these circulating virus-specific T cells have features of recently activated naive T cells in that they coexpress CD45RA and CD45R0 and appear to be in the cell cycle. In contrast, in people who have recovered from CMV infection earlier in life, virus-specific T cells do not cycle and express surface markers characteristic of memory T cells. After the initial rise, circulating virus-specific CD4(+) T cells decline rapidly. During this phase, a strong rise in IgM and IgG anti-CMV antibody titers occurs, concomitant with the reduction of CMV-DNA in the circulation.

CD4-Positive T-Lymphocytes↗
PubMed1999

Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy.

BACKGROUND: A stable reservoir of latently infected, resting CD4 T cells has been demonstrated in HIV-1-infected patients despite prolonged antiretroviral treatment. This is a major barrier for the eradication of HIV by antiretroviral agents alone. Activation of these cells in the presence of antiretroviral therapy might be a strategy to increase the turnover rate of this reservoir. METHODS: Three HIV-1-positive patients on potent antiretroviral therapy, in whom plasma viremia had been suppressed to below 5 copies/ml for at least 26 weeks, were treated with a combination of OKT3 (days 1-5) and recombinant human IL-2 (days 2 6). RESULTS: The side-effects were fever, headache, nausea, diarrhea, and in one of the patients transient renal failure and seizures. The regimen resulted in profound T cell activation. In one patient plasma HIV-1 RNA transiently increased with a peak at 1500 copies/ml. In the other two patients plasma HIV-1 RNA levels remained below the detection limit, but HIV-1 RNA levels in the lymph nodes increased two- to threefold. All patients developed antibodies against OKT3. CONCLUSION: OKT3/IL-2 resulted in T cell activation and proliferation, and could stimulate HIV replication in patients having achieved prolonged suppression of plasma viremia. OKT3/IL-2 therapy was toxic and rapidly induced antibodies against OKT3.

Anti-HIV Agents↗
PubMed1999

Interferon-gamma preferentially reduces memory/effector CD8 T lymphocytes in healthy subjects.

To evaluate the influence of interferon-gamma (IFN-gamma) on leukocyte dynamics, with a focus on naive and memory T cells, we studied 6 healthy subjects twice in a placebo-controlled trial: once after the administration of recombinant human IFN-gamma (rhIFN-gamma; 100 microg/m2 subcutaneously) and at least 4 weeks later, after the administration of saline solution. Additionally, we studied the expression of adhesion molecules on T lymphocytes after in vitro incubation of whole blood with rhIFN-gamma. IFN-gamma induced a significant depletion in the number of T lymphocytes (P < .05 vs control), which was more severe in the CD8+ cell subset than in the CD4+ T cell subset. The numbers of naive CD4+ T cells and memory CD4+ T cells were equally affected by IFN-gamma, whereas within the CD8+ T cell subset, memory/effector cells disappeared preferentially as compared with naive cells (P < .05 vs control). In addition, IFN-gamma induced a decrease in B cells, NK cells, and monocytes. After an initial increase, granulocyte counts decreased significantly as compared with controls. These effects appeared not to be caused by the minimal rise in plasma cortisol levels (P < .05 vs control). In vitro, IFN-gamma did not up-regulate the expression of CD11a, NKI L16, CD11b, LFA-3, or VLA-4. We conclude that the administration of a single dose of IFN-gamma to healthy subjects profoundly affects the numbers of several leukocyte subsets in the peripheral blood compartment.

Adult↗
PubMed1999

Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis).

BACKGROUND: Effective treatment modalities for systemic sclerosis, a life-threatening and disabling disease, are still lacking. Possible efficacy of photopheresis has been reported in several studies. Because of the complexity of the treatment, placebo-controlled trials are difficult to perform. OBJECTIVE: We investigated the effect of photopheresis on clinical parameters (skin score and internal organ functions), immunologic parameters, and quality of life. METHODS: Nineteen patients with progressive systemic sclerosis of less than 5 years' duration were randomized into 2 groups. One group (group A) received photopheresis for 1 year, the other group (group B) received no treatment at all. After 1 year the groups switched (crossover design). Photopheresis was performed on 2 consecutive days every 4 weeks; the psoralens were administered parenterally. The main outcome parameter was the skin score after 1 year of treatment compared with that of the control group. RESULTS: The average skin score improved with 5.4% (standard error [SE], 20. 8%) in group A and deteriorated with 4.5% (SE, 13.8%) in group B (not significant; P =.71). Before crossover, the average increase in skin score was 5.3% (means of entire group). No change was observed in other clinical parameters. Approximately 1 year after crossover, the skin score reversed to what would have been expected with an average increase of 5.3% per year. There was also no effect on immunologic parameters. Quality of life did not change during treatment. CONCLUSION: We were not able to show that photopheresis, performed as described above, is an effective treatment in systemic sclerosis. The difference in average skin score was statistically and clinically insignificant. Despite the small sample size, we concluded that the magnitude of the observed changes is too small to justify photopheresis as a regular treatment.

Adult↗
PubMed1999

Expression of granzyme B during primary cytomegalovirus infection after renal transplantation.

CD8+ T cells employ granzyme B (GrB) to induce apoptosis in target cells. Increased expression of GrB has been put forward as a diagnostic marker in transplant rejection and viral infection. Three-color flow cytometric analysis revealed that peripheral blood CD8+ T lymphocytosis during primary cytomegalovirus infection after renal transplantation resulted from expansion of a CD8+GrB+CD62L+ T cell subset that was almost absent during stable transplant function or acute rejection. This expansion coincided with a temporary increase in systemic soluble GrB (sGrB) levels. No such increase was observed during stable transplant function or acute rejection. Thus, the primary immune response to cytomegalovirus infection is accompanied by appearance of CD8+GrB+CD62L+ T cells and increased sGrB levels in the peripheral blood compartment. Determination of the latter may provide a novel approach for monitoring viral infections.

Adolescent↗
PubMed1999

CD4dullCD8bright double-positive T-lymphocytes have a phenotype of granzyme Bpos CD8pos memory T-lymphocytes.

BACKGROUND: T-lymphocytes that co-express CD4 and CD8 antigens may be found in small percentages in the peripheral blood of healthy individuals, and have a CD4brightCD8dull phenotype. CD4dullCD8bright T-lymphocytes have been found only in temporal association with some viral infections. METHODS: Four-colour flow cytometric analysis of peripheral blood mononuclear cells from a renal transplant recipient with cytomegalovirus infection was performed. RESULTS: A small but clearly distinguishable subpopulation of CD4dullCD8bright double-positive T-lymphocytes was detected, that exhibited phenotypic characteristics of cytotoxic T-lymphocytes and were granzyme B positive. Furthermore, no naive cells appeared to be present within this subpopulation. CONCLUSIONS: CD4dullCD8bright double-positive T-lymphocytes are enriched for memory and effector cytotoxic T cells.

CD4 Antigens↗
PubMed1999

Interferon-gamma has immunomodulatory effects with minor endocrine and metabolic effects in humans.

To evaluate whether interferon-gamma (IFN-gamma) is involved in the interaction between the immune and endocrine systems in vivo, we studied six healthy subjects twice in a placebo-controlled trial: once after administration of recombinant human IFN-gamma and, on another occasion, after administration of saline. The rate of appearance of glucose was determined by infusion of [6,6-2H2]glucose and resting energy expenditure by indirect calorimetry. Human leukocyte antigen-DR gene expression on monocytes and serum neopterin increased after administration of IFN-gamma (P < 0.05 vs. control). IFN-gamma increased serum interleukin-6 levels significantly. Levels of tumor necrosis factor-alpha remained below detection limits. IFN-gamma increased plasma concentrations of ACTH and cortisol (P < 0.05 vs. control), IFN-gamma did not alter concentrations of growth hormone, (nor)epinephrine, insulin, C peptide, glucagon, or insulin-like growth factor I. IFN-gamma did not alter plasma concentrations of glucose and free fatty acids nor the rate of appearance of glucose. IFN-gamma increased resting energy expenditure significantly. We conclude that IFN-gamma is a minor stimulator of the endocrine and metabolic pathways. Therefore, IFN-gamma by itself is probably not a major mediator in the interaction between the immune and the endocrine and metabolic systems.

Adjuvants, Immunologic↗
PubMed1998

Mechanisms of lymphocyte-mediated cytotoxicity in acute renal allograft rejection.

BACKGROUND: Graft-infiltrating T-cell (GIC) lines cultured from biopsies obtained during acute renal allograft rejection exhibit donor-specific cytotoxicity toward proximal tubular epithelial cell (PTEC) lines cultured from corresponding biopsies. This system allows for study of the relative contributions of perforin/granzyme B (GrB)- and Fas ligand (FasL)-based cytotoxicity to killing of PTEC. METHODS: Expression of perforin, GrB and FasL was analyzed by immunocytochemical staining of cytocentrifuge preparations of GIC lines cultured from 10 renal allograft biopsies. Specific inhibitors of the perforin/GrB- and FasL-based pathways were used in 51Cr release and apoptosis assays to determine their relative contributions to cytotoxicity of GIC lines toward corresponding donor PTEC lines. RESULTS: Cells with a strong granular pattern were observed upon immunocytochemical staining of GIC lines with anti-perforin or anti-GrB monoclonal antibodies. A diffuse staining pattern was observed upon staining with anti-FasL polyclonal antibodies. Six of eight GIC lines cultured from biopsies with acute rejection showed cytotoxicity toward corresponding donor PTEC lines, whereas two GIC lines cultured from biopsies without rejection did not. Preincubation of cytotoxic GIC lines with concanamycin A, an inhibitor of the perforin/GrB-based pathway, caused inhibition of both lysis and apoptosis of PTEC. Inhibition was not observed upon incubation with monoclonal antibodies that inhibit Fas. CONCLUSIONS: The perforin/GrB-based pathway is mainly responsible for cytotoxicity of GIC lines toward corresponding donor PTEC lines, suggesting that this pathway predominates in tubular epithelial cell destruction by cytotoxic T lymphocytes during acute renal allograft rejection in vivo.

Acute Disease↗