摘要:

AbstractDAB486IL‐2 is an interleukin‐2 receptor‐specific cytotoxin which selectively targets and kills cells which bear the high‐affinity form of the IL‐2 receptor. Since elimination of activated T lymphocytes may be useful in the treatment of rheumatoid arthritis, the effect of DAB486IL‐2 treatment in an animal model of arthritis was investigated. We demonstrated that rats treated with DAB486IL‐2 during the induction phase of disease have delayed onset of symptoms and significantly reduced severity of inflammation as well as a depressed proliferative response to mycobacterial stimulationin vitro.In addition, the presence of preexisting antibodies to the molecule had no impact on the anti‐arthritic effects observed in this model. These data suggest that DAB486IL‐2 may have therapeutic potential in the treatment of rhe

ISSN:0014-2980    

DOI:10.1002/eji.1830220702

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractDespite reports on the secretion of granulocyte — macrophage — colony‐stimulating factor (GM‐CSF) by murine peritoneal macrophages in response to inflammatory stimuli, the ability of human monocytes to generate this growth factor has remained doubtful. Neither endotoxin, phorbol compounds, nor inflammatory cytokines have been shown to elicit GM‐CSF by these cells. Our present studies indicate that exposure of monocytes to solid‐phase murine IgG2a, but not to murine IgG1and thus cross‐linkage of the 72‐kDa FcγRI results in transcription of the GM‐CSF gene, accumulation of stable GM‐CSF mRNA and finally in release of biologically active GM‐CSF protein. Cross‐linking of FcγRI by a murine anti‐FcγRI monoclonal antibody and goat anti‐mouse antibody failed, however, to stimulate GM‐CSF release. This suggests that high affinity Fc‐FcγRI interactions are required for induction o

ISSN:0014-2980    

DOI:10.1002/eji.1830220703

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractThymocytes can be rendered tolerant by non‐deletional mechanisms upon interaction with major histocompatibility complex (MHC) antigens on thymic epithelium. Whether the epithelial cells in the cortex or medulla could mediate this effect was not clear so far. To address this question, a transgenic mouse was generated in which the bovine keratin IV promoter was used to control expression of the alloantigen Kb. In the periphery the Kbtransgene was expressed on a subset of keratinocytes. In the thymus expression was restricted to a subpopulation of medullary epithelial cells. No expression was found in the cortex. Such a tissue distribution has been reported for the keratin IV molecule demonstrating the faithfulness of the promoter used here.To follow the fate of the Kb‐reactive thymocytes, this mouse was mated with another transgenic mouse expressing an anti‐KbT cell receptor (TcR). In the double‐transgenic mice the CD8+CD4−thymocytes were not deleted but they were found to be anergic as assayed by their failure to be activatedin vitroby either Kb‐positive spleen cells or by cross‐linked anti‐TcR antibodies. These observations establish that expression of an MHC class I antigen in the thymic medullary epithelium is sufficient to induce anergy in the mature CD8+CD4−thy

ISSN:0014-2980    

DOI:10.1002/eji.1830220704

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractMice homozygous for thegld(generalized lymphoproliferative disease) mutation develop systemic autoimmune disease and severe lymphadenopathy due to an age‐related accumulation in the peripheral lymphoid organs of polyclonal T cells bearing a unique phenotype (CD4−CD8−TCR αβ+B220+). These T cells overex‐press T cell receptor (TcR) αβ chain RNA, proto‐oncogenes c‐myb and fyn, and proliferate poorly in response to TcR‐mediated stimulation. The origin of these T cells is poorly understood. To study the influence of a functionally rearranged TcR β chain on the T cell developmental abnormality of thegldmutation and autoimmunity, we have backcrossed TcR Vβ8.1‐transgenic mice to C3H‐gld/gldto homozygosity (transgenic gld mice). In transgenic gld mice, lymphadenopathy was markedly inhibited and the accumulation of CD4−CD8−T cells did not occur, although the remaining T cells overexpressed c‐myb and proliferated poorly in response to TcR occupancy. These features indicate that the pattern of proto‐oncogene expression and abnormal function persist in phenotypically normal T cells in transgenic gld mice, and that these characteristics can be dissociated from the accumulation of CD4−CD8−T cells. The hypergammaglobulinemia and anti‐double‐stranded DNA (anti‐dsDNA) antibody production was partially improved in transgenic gld mice, supporting the critical role of T cells in abnormal B cell activation described in autoimmunity‐prone mice. To investigate further the mechanisms underlying the inhibition of CD4−CD8−T cell accumulation in transgenic gld mice, the fetal ontogeny of T cells in transgenic mice was compared with that of non‐transgenic mice. In transgenic thymus, development of TcR αβ+cells was accelerated as detected by earlier expression of CD4, CD8 and TcR in fetal thymus. In contrast, the number of TcR γδ+cells was reduced. We suggest that altered T cell development in transgenic mice directly or indirectly inhi

ISSN:0014-2980    

DOI:10.1002/eji.1830220705

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractMouse and human natural IgM autoantibodies have been shown to be polyreactive and “connected” through V region‐dependent interactions. In the present study, we have identified a connected subfraction of normal human serum IgG by using affinity chromatography of F(ab′)2fragments of pooled IgG (IVIg) or of IgG from a single donor on Sepharose‐bound F(ab′)2fragments of the same source of IgG. The connected fraction of IgG exhibited a high content of autoantibodies directed against a wide panel of evolutionarily conserved self antigens and of self antigens that may be targets of autoantibodies in autoimmune diseases. Connected IgG also contained higher amounts of antibodies directed against commonly encountered microbial antigens than unfractionated IgG. The connected fraction did not, however, differ from unchromatographed IgG nor from non‐connected IgG in its content of antibodies to vaccinal antigens and to distant foreign antigens. Thus, in humans as in mice, connectivity is a prominent feature of autoantibodies. Our observations are suggestive of a tight control by IgG of the expressed autoreactive repertoire in healthy individuals and strengthen the concept that the therapeutic infusion of pooled normal IgG (IVIg) may be effective in autoimmune diseases by bringing to patients normal regulatory components of the immunoglo

ISSN:0014-2980    

DOI:10.1002/eji.1830220706

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractWe show that interleukin (IL)‐2 is necessary and sufficient for the proliferation of both CD4 and CD8 subsets of peripheral murine T cells activated by plastic‐bound anti‐CD3 monoclonal antibodies (mAb). The frequency of proliferating cells (f) was 0.32 for CD4 cells and 0.63 for CD8 cells. These frequencies were not increased by the addition of IL‐1 or IL‐6, alone or in combination. These cytokines were unable to induce responsiveness to IL‐2 in T cells confirming that they cannot substitute for the signal delivered via the TcR/CD3 complex. On the other hand, IL‐1 and IL‐6 increase the growth rate of CD4 cells. The addition of IL‐6 significantly lowered the mean doubling time (dt) of CD4 cells (dt: 26 hvs.38 h in the presence of IL‐2 alone,p<0.01), while the addition of IL‐1, ineffective by itself, combined with IL‐6 further increased the growth rate of CD4 cells (dt: 23 h,p<0.001). The growth rate of CD8 cells stimulated with anti‐CD3 and IL‐2, was markedly faster than that of CD4 cells (dt: 18 hvs.38 h,p<0.001) and was not significantly influenced by a

ISSN:0014-2980    

DOI:10.1002/eji.1830220707

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractCD5+B cells in cattle are present in peripheral blood and spleen, but not in lymph nodes, tonsils or Peyer's patches. Compared to classical B cells, they express similar levels of B cell surface markers, but have higher levels of surface IgM. We failed to find evidence for IgD on bovine B lymphocytes. The CD5+B cells expressed CD11b (Mac‐1). Another small subpopulation of B cells carried CD11b but not CD5. In cattle infected withTrypanosoma congolense, a dramatic increase in the percentage of CD5+B cells in blood and spleen was observed. This increase occurred 7‐10 days after parasites were first detected in the blood and correlated with the increase in serum IgM and the increase in the absolute number of B cells that is typical to trypanosome‐infected animals. The increase in B cells was found to be due mainly to the expansion of the CD5+B cell subpopulation. The cause of the amplification of the CD5+B cells and their possible involvement in the production of autoantibodies and non‐parasite‐specific antibodies which have been described in trypanosome‐infected animals ar

ISSN:0014-2980    

DOI:10.1002/eji.1830220708

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractThe molecular mechanisms leading to anti‐double‐stranded (ds)DNA antibody production in systemic lupus erythematosus (SLE) are poorly understood. We describe here the immunoglobulin variable region genes of six human hybridomas secreting IgG anti‐dsDNA antibodies derived from three SLE patients. The monoclonal IgG anti‐dsDNA antibodies have been shown to be of high affinity and no multireactivity was observed (Winkler et al.,Clin. Exp. Immunol., 1991.85:379). The comparison of the variable region genes expressed in the hybridomas with known germ‐line genes as well as with the germ‐line counterparts from one patient shows that the VHand VLsequences are somatically mutated. The pattern and extent of the observed somatic mutations are suggestive for an antigen‐driven selection of at least four of these B cell clones. Several VHand VLgenes used by the hybridomas were found to be expressed in the natural antibody repertoire, in the restricted fetal repertoire and in B cell malignancies expressing th

ISSN:0014-2980    

DOI:10.1002/eji.1830220709

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractThe molecular events during the anti‐tumor response induced by interleukin (IL)‐4 were investigated by quantitative polymerase chain reaction. The growth of Chinese hamster ovary cells transfected to produce IL‐4 (CHO.T1) was strongly suppressed when cells were injected intraperitoneally into nude mice and this suppression was accompanied by the rapid accumulation of activated macro‐phages. Peritoneal cells from such mice were analyzed for mRNA induced by IL‐4. Correlating with a high local IL‐4 concentration, several transcripts were found to be up‐regulated during the early phase of the anti‐tumor response [IL‐4 receptor, IL‐5, tumor necrosis factor (TNF) and interferon (IFN)‐γ]. The functional relevance of the elevated mRNA levels was analyzed by injection of CHO.T1 cells together with anti‐cytokine monoclonal antibodies (mAb). In contrast to anti‐IL‐5 and anti‐TNF mAb, an anti‐IFN‐γ mAb interfered with the anti‐tumor response demonstrating the involvement of IFN‐γ during the IL‐4‐induced tumor suppression. Tumor growth in anti‐IFN‐γ mAb‐treated animals was significantly delayed in comparison to anti‐IL‐4 mAb‐treated mice, suggesting t

ISSN:0014-2980    

DOI:10.1002/eji.1830220710

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY

摘要:

AbstractSevere combined immunodeficient (scid) mice are deficient in functional T cells and B cells. Hence, scid mice reconstituted with human peripheral blood leukocytes (scid‐huPBL) provide an excellent model for analysis of the human immune response underin vivoconditions. We have investigated this model further by analyzing human immune responses in the progeny of scid‐huPBL (termed scid‐humo). We find markedly elevated levels of human immunoglobulins (Ig) in the serum of scid‐humo for more than 12 weeks indicating materno‐fetal transfer of human B lymphocytes. Consistent with this finding we obtained evidence for the existence of human lymphocytes in scid‐humo. Murine Ig levels in scid‐humo were also elevated and surface Ig‐expressing cells (probably B cells) were demonstrable. In this respect scid‐humo resembled “leaky” scid. In contrast to “leaky” scid, scid‐humo accepted transfer of human blood leukocytes. Not only leukocytes from autologous but also those from heterologous donors were accepted. Human Ig levels in scid‐humo increased more rapidly as compared to normal scid mice. Thus, despite these increased B cell activities in scid‐humo, transferred human leukocytes were not affected indicating that materno‐fetal transfer of human cells had caused tolerization or conditioning. This is in contrast to scid mice in which elevated Ig levels correlate with increased failure rates of reconstitution with human blood leukocytes. We propose that scid‐humo provide an improved model for studying the human i

ISSN:0014-2980    

DOI:10.1002/eji.1830220711

出版商:WILEY‐VCH Verlag GmbH    

年代:1992

数据来源: WILEY