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Biomedical subjects

F H Gmelig-Meyling

Publications and source records attributed to F H Gmelig-Meyling.

At least 19 recordsLinked to original sources
PubMed2001

No association between IL-10 promoter gene polymorphism and heart failure or rejection following cardiac transplantation.

Expression of interleukin (IL)-10 influences the frequency of rejection events after organ transplantation. Therefore, 70 heart transplant patients were genotyped for three single nucleotide polymorphisms and a microsatellite polymorphism in the promotor region of the IL-10 gene. The promoter region was amplified by polymerase chain reaction and genotyped by a colorometric oligo ligation assay and gene scan analysis, respectively. Patient groups consisted of patients suffering from dilated cardiomyopathy or ischaemic heart disease. Cardiac donors served as control group. No correlation was found between genotypes and heart failure or rejection after heart transplantation. This may indicate that in heart transplantation, the total balance of cytokine production is more important for post-transplant rejection activities than the levels of IL-10 as such.

Gene Expression↗
PubMed2000

High frequency of IL-4 producing helper T lymphocytes associated with a reduced incidence of heart allograft rejection.

The reduction in the frequency of rejection episodes several months after heart transplantation (HTX) correlates with the development of donor-specific nonresponsiveness. This is reflected in a reduced frequency of donor-specific cytotoxic T cells (CTL) in the peripheral blood. We investigated whether the reduced CTL frequency and the incidence of rejection episodes coincided with a change in the frequency of either IL-2- or IL-4-producing helper T lymphocytes (HTL). We measured the frequency of HTL before and at several time points after HTX in the blood of ten recipients, using limiting dilution analysis for IL-2 and IL-4. In most patients, HTL frequencies dropped immediately after transplantation, but returned to pre-HTX values later after transplantation. No consistent decrease or increase in frequencies was observed long after HTX. In contrast to IL-2, the HTL frequencies for IL-4 before transplantation were significantly higher in patients without post-HTX rejection episodes requiring treatment than in patients with such episodes. This phenomenon was observed for the in vitro responses towards both donor and third-party cells. In conclusion, relatively high frequencies of IL-4-producing T cells may have a beneficial effect on the outcome of human heart transplantation, because they are associated with a reduced incidence of rejection episodes after transplantation.

Biomarkers↗
PubMed1998

T cell apoptosis in human heart allografts: association with lack of co-stimulation?

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation.

Antigens, CD↗
PubMed1997

Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease.

OBJECTIVES: To compare peripheral type 1 (T1) and type 2 (T2) T cell activities in rheumatoid arthritis (RA) patients with that found for osteoarthritic (OA) patients and healthy controls and to correlate peripheral T1/T2 cell activity in RA with parameters of the disease. METHODS: Peripheral blood mononuclear cells were isolated from patients with RA (n = 66), OA (n = 19), and healthy controls (n = 15). Primary T cell activity in these mononuclear cells was enhanced by means of anti-CD3/anti-CD28, which mimicks stimulation of T cells by activation of the T cell receptor and a major co-stimulatory signal. Interferon gamma (IFN gamma) production and interleukin 4 (IL4) production in the three groups were quantified as measures of T1 and T2 cell activity, respectively, and compared. Serum tumour necrosis factor alpha (TNF alpha), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and joint destruction assessed radiographically of RA patients were determined as parameters of disease activity and correlated with T1/T2 cell activity. RESULTS: Peripheral T cells from RA patients produced significantly less IFN gamma and more IL4 than T cells from both age and sex matched OA patients and healthy controls. Moreover, in RA patients both a decrease in IFN gamma and an increase in IL4 production correlated with an increase in serum TNF alpha, ESR, CRP, and joint destruction. CONCLUSIONS: These results suggest a role for differential T cell activity in RA. In view of the intra-articular T1 cell predominance the results might be explained by selective T1 cell migration into the joint or peripheral suppression of T1 cell activity.

Aged↗
PubMed1997

Cytokine messenger RNA expression by donor-specific cytotoxic T-cell clones after allogeneic heart transplantation.

BACKGROUND: After heart transplantation, expression of various cytokines can be detected in endomyocardial biopsy specimens both in the presence and in the absence of rejection. In this study we have analyzed the contribution of donor-specific CD8+ cytotoxic T cells to intragraft cytokine expression. METHODS: T cells were propagated from endomyocardial biopsy specimens in medium containing interleukin-2 and interleukin-4. From the T-cell lines obtained, T-cell clones were generated by limiting dilution. A number of 15 CD8+ donor-specific cytotoxic T-cell clones were generated from a single T-cell line and were analyzed for their cytokine messenger RNA expression. The cytokine profile of the clones was studied on the mRNA level by reverse transcriptase polymerase chain reaction. RESULTS: Almost all clones expressed mRNA for interleukin-1 beta, interleukin-4, and interleukin-10, and 75% of the clones expressed mRNA for interleukin-1 alpha, interleukin-9, and tumor necrosis factor-beta. In about half of the clones expression of interleukin-2, interleukin-6, interleukin-8, and interferon-gamma was detected. Tumor necrosis factor-alpha was only detected in one of the clones. The cytokine profiles exhibited a considerable heterogeneity. The 15 clones had previously been analyzed for their T-cell receptor V beta-gene family expression and T-cell receptor V-D-J region sequence. Homology in the V-D-J regions of the clones indicated that the 15 clones were derived from a limited number of progenitor cells. Interestingly, clones derived from one progenitor expressed a different mRNA cytokine profile. CONCLUSIONS: This study shows that donor-specific cytotoxic T cells can contribute to the spectrum of locally produced cytokines. The cytokine expression of these cytotoxic T cells seems not to be limited to a distinct profile.

CD8-Positive T-Lymphocytes↗
PubMed1996

Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4.

OBJECTIVE: Inflammation-induced articular cartilage degradation is a major problem in rheumatoid arthritis (RA). Type 1 T cell activity (characterized by interferon-gamma/interleukin-2 [IL-2] production), and consequently, the production of the proinflammatory cytokines IL-1 and tumor necrosis factor alpha (TNF alpha), have been reported to play a major role in cartilage damage. IL-10 and IL-4, both produced by type 2 T cells, are cytokines with the capacity to down-regulate proinflammatory responses. The present study was undertaken to investigate the way in which these cytokines affect activated mononuclear cells (MNC) of RA patients in relation to human articular cartilage degradation in vitro. METHODS: MNC from synovial fluid and peripheral blood of RA patients were stimulated with bacterial antigen and treated with IL-10 and/or IL-4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL-1/TNF alpha-dependent cartilage damage. Cytokine production and effects of conditioned media, as well as effects of IL-10 and IL-4 on proteoglycan (PG) turnover (as a measure for cartilage damage), were determined. RESULTS: IL-10 and IL-4 inhibited proinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimulated RA MNC. IL-10 was more potent than IL-4 in this respect, and the combination of IL-10 and IL-4 had an additive effect. In addition, IL-10 directly stimulated cartilage PG synthesis. CONCLUSION: IL-10 reverses the cartilage degradation induced by antigen-stimulated MNC, and IL-4 has an additive effect on this process. Furthermore, IL-10 has a direct stimulatory effect on PG synthesis, and IL-4, as a growth factor for type 2 T cells, can reduce the ratio of type 1 to type 2 T cell activity. These results provide evidence in favor of the use of a combination of the two cytokines in the treatment of RA.

Adult↗
PubMed1996

Search for the antigen-specificity of homogeneous IgG components (H-IgG) after allogeneic bone marrow transplantation.

After allogeneic BMT, transient homogeneous Ig components (H-Ig) can be detected in the sera of most graft recipients. So far, data on the antigen-specificity and therefore the function of these H-Ig are not available. Such information may be important for our understanding of the underlying mechanisms that are responsible for these excessive clonal B cell expansions, and it may help to delineate the functional antibody repertoire after BMT. In the present study, sera of 98 paediatric BM graft recipients were investigated for the potential presence of H-Ig of IgG isotype (H-IgG) with specificity towards a panel of antigens, including vaccine and herpes virus antigens, auto-antigens and allo-antigens. The vast majority of H-IgG in sera of BM graft recipients were unreactive when tested for this panel of antigens. However, in four cases, antigen-specificity of H-IgG to tetanus toxoid could be demonstrated after vaccination with that antigen. An explanation for the negative findings may be either that a restricted antibody production had been elicited by other non-tested antigens, eg substances of colonizing and translocating bacteria or of food antigens, or that the H-IgG components may have anti-idiotype or anti-'self' specificity.

Adult↗
PubMed1995

Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients.

OBJECTIVE: Fc gamma receptors of class IIa (Fc gamma RIIa) occur in 2 allelic forms, with either a low (IIa-R131) or a high (IIa-H131) affinity for complexed IgG2 and IgG3. This polymorphism might have implications for the handling of immune complexes. Therefore, we determined the distribution of the Fc gamma RIIa allotypes in patients with systemic lupus erythematosus (SLE), with or without a history of lupus nephritis. METHODS: We studied 95 unrelated white European patients with SLE, as defined by the American College of Rheumatology criteria, 50 of whom had a history of lupus nephritis, and 69 healthy white European control subjects. Fc gamma RIIa allotypes were determined by immunophenotyping of blood monocytes. RESULTS: It was found that lupus nephritis was significantly associated with the "low affinity" Fc gamma RIIa R/R131 allotype and with the R131 allele, compared with healthy controls. No significant association was found upon comparison of groups with and without nephritis. CONCLUSION: SLE patients with a history of lupus nephritis have an abnormal distribution of Fc gamma RIIa allotypes. Fc gamma RIIa may well play a role in the pathogenesis of lupus nephritis, since IIa-R/R131 SLE patients seem to have a higher incidence of developing this complication.

Adult↗
PubMed1995

Prevention of donor-specific T-cell unresponsiveness after buffy-coat-depleted blood transfusion.

The immunosuppressive effect of blood transfusions has been demonstrated in several clinical studies. The effect is probably mediated by HLA-class-II-bearing donor leucocytes, because results from laboratory tests show specific down-regulation of the recipient's T-Cell response after administration of blood from donors sharing one HLA haplotype with the recipient. In the present study we evaluated the immunosuppressive potential of buffy-coat-depleted red cell transfusions in patients waiting for renal transplantation, by measuring the frequency of cytotoxic precursor T cells before and after transfusion. The buffy coat was removed from whole blood by the Optipress system and resulted in > 97% depletion of lymphocytes and monocytes. A single transfusion of HLA-haplotype-matched buffy-coat-depleted red cells induced donor-specific down-regulation of T-cell responses in only two of 14 patients. Since HLA-class-II-bearing cells are also involved in the induction of anti-HLA antibodies, we evaluated retrospectively the incident of HLA alloimmunization after a single transfusion of buffy-coat-depleted red cells. No anti-HLA antibodies were found in 140 patients at risk for primary immunization. We conclude that the poor immunological responses found after a single transfusion of HLA-haplotype-matched buffy-coat-depleted red cells is due to the small number of residual HLA-class-II-bearing donor cells. This blood component should not be used for induction of immunosuppression.

Cell Separation↗
PubMed1994

Reduction of donor-specific cytotoxic T lymphocyte precursors in peripheral blood of allografted heart recipients.

Tolerance to allografted hearts in human recipients has been observed both in clinical situations and in in vitro experiments. To elucidate whether a quantitative change of alloreactive CTL is one of the mechanisms accounting for this graft tolerance, CTL precursor (CTLp) frequencies in the peripheral blood of 10 heart recipients were measured against spleen cells from donors and HLA nonidentical third-party persons. In this longitudinal follow-up study, we showed that the rejection reaction(s) in the grafted heart correlated with CTLp frequencies in samples taken before transplantation against the donor spleen cells, but not with the CTLp frequencies against the spleen cells from the third-party persons. The CTLp frequencies against the spleen cells from donors decreased 4-6 months after transplantation, and remained at a low level afterward. However, the CTLp frequencies against spleen cells from third-party persons in blood samples obtained 1 year after transplantation were not significantly different from those before transplantation. Therefore, we conclude that donor-reactive CTLs are important in rejecting allografted heart. The decrease in donor-specific CTLp after transplantation could explain the donor-specific tolerance. The decrease may be due to homing of the specific CTLp to the graft, or by clonal deletion of the donor-reactive CTL caused by chronic alloantigen stimulation in the presence of immunosuppressive therapies.

Blood Cells↗
PubMed1992

A human systemic lupus erythematosus-related anti-cardiolipin/single-stranded DNA autoantibody is encoded by a somatically mutated variant of the developmentally restricted 51P1 VH gene.

We report the Ig H and L chain V region sequences from the cDNAs encoding a monoclonal human IgG anti-cardiolipin/ssDNA autoantibody (R149) derived from a patient with active SLE. Comparison with the germ-line V-gene repertoire of this patient revealed that R149 likely arose as a consequence of an Ag-driven selection process. The Ag-binding portions of the V regions were characterized by a high number of arginine residues, a property that has been associated with anti-dsDNA autoantibodies from lupus-prone mice and patients with SLE. The VH gene encoding autoantibody R149 was a somatically mutated variant of the 51P1 gene segment, which is frequently associated with the restricted fetal B cell repertoire, malignant CD5 B cells, and natural autoantibodies. These data suggest that in SLE patients a common antigenic stimulus may evoke anti-DNA and anti-cardiolipin autoantibodies and provide further evidence that a small set of developmentally restricted VH genes can give rise to disease-associated autoantibodies through Ag-selected somatic mutations.

Amino Acid Sequence↗
PubMed1992

Expression of members of the immunoglobulin VH3 gene families is not restricted at the level of individual genes in human chronic lymphocytic leukemia.

Previous studies on the repertoire of Ig VH genes utilized in the malignant cells of chronic lymphocytic leukemia (CLL) have suggested a non-random expression pattern. In particular, individual genes from the VH1, VH5, and VH6 gene families have been frequently found in CLL. With regard to other VH gene families, including the large VH3 family which is expressed in greater than 50% of CLL cases, it is unknown whether CLL cells utilize either a broad or a restricted repertoire of VH genes. In the present paper, we analyzed the VH genes expressed in a collection of 11 CLL cases. The results of these experiments demonstrate that there is no apparent restriction in the usage of individual members of the VH3 gene families in CLL.

Base Sequence↗
PubMed1992

Molecular approaches to the study of human B-cell and (auto)antibody repertoire generation and selection.

We have shown that the restricted repertoire of VH genes expressed in second trimester human fetal liver is not solely determined by JH proximity. Furthermore, by following the fate of two VH gene segments in different B-cell repertoires, we have provided evidence that multiple factors contribute to the frequency with which individual VH genes are utilized. We found that the repertoire of adult blood IgM-bearing B cells contains a high proportion of B lymphocytes that express extensively mutated VH genes. Finally, we show that somatically-mutated variants of particular VH and VL genes that, in germline configuration, are frequently found in the early B-cell repertoire and in natural autoantibodies, encode pathogenic IgG autoantibodies characteristic of human SLE. These VH and VL genes harbor all the characteristics of an antigen-driven B-cell activation and selection process.

Amino Acid Sequence↗
PubMed1991

Antibody specificity and immunoglobulin VH gene utilization of human monoclonal CD5+ B cell lines.

Human B lymphocytes that bear the CD5 antigen are relatively abundant in early ontogeny and comprise a small fraction of the B cell population in adults. The CD5 B cell subset has attracted much attention because of its possible involvement in autoimmune disease and certain B cell malignancies. To begin to understand the role of CD5 B cells in disease processes, we have generated a panel of ten human monoclonal B cell lines selected for expression of the CD5 antigen. These cell lines were obtained by Epstein-Barr virus transformation of B lymphocytes isolated from the spleen, liver and bone marrow of a 19-week-old fetus, from cord blood and from peripheral blood of healthy volunteers. In addition, one cell line was isolated from the spleen of a patient with chronic lymphocytic leukemia. Here, we describe the antibody and immunoglobulin VH gene repertoire of this panel of CD5 B cell lines. The results of these experiments show that (a) some but not all CD5 B cell lines secrete polyreactive antibodies that bind to a variety of self- and xenoantigens and (b) members of the small VH4, VH5 and VH6 gene families are overrepresented in this panel of cell lines. Nucleotide sequence analysis revealed the expression of VH gene elements that have been previously reported in the preimmune B cell repertoire, in CD5 B cell tumors and in polyreactive antibodies.

Antibody Specificity↗