摘要:

AbstractThe phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin‐mediated shock, was tested for its immunosuppressive potential on T lymphocyte activationin vitroandin vivo.POX was found to have a profound inhibitory effect on both mitogen‐ and antigen‐induced proliferation of CD4+T cellsin vitro.This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedlyin vitrostimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX could drastically down‐regulate tumor necrosis factor regulate production and to a lesser extent interleukin (IL)‐2 secretion in activated T cells, but an excess of exogenous IL‐2 did not override the antiproliferative effect of the drug. In contrast, the same doses of POX had no inhibitory effect on spontaneous or induced IL‐4 and IL‐6 production by short‐term cultured T lymphocytes, indicating a selective sparing of T helper type 2 (Th2)‐associated lymphokine functions by the drug. To test a potential use of POX as an antiinflammatory agent in T cell‐mediated autoimmune disease, the influence of POX on myelin basic protein (MBP)‐induced experimental autoimmune encephalomyelitis (EAE) was assessed. The onset of EAE in Lewis rats could almost completely be abrogated by oral administration of POX during the induction phase of disease. Lack of clinical symptoms in POX‐treated animals coincided with a marked suppression of MBP‐specific T cell reactivityin vitro, without any evidence for a generalized impairment of T cell activity. Collectively, our data suggest the potential use of xanthine derivatives of the POX type as a supporting antiinflammatory therapeutic agent in Th1 CD4+T cell‐mediated autoimmune diseases in anim

ISSN:0014-2980    

DOI:10.1002/eji.1830230802

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractEnhancement of major histocompatibility complex (MHC) class I expression leads to protection from recognition by natural killer (NK) cells in several systems. MHC class I gene products can be expressed in different forms at the cell surface ‐ for example as “empty” β2‐microglobulin (β2m)‐associated heterodimers or free heavy chains. To study the role of different class I heavy chain forms in NK target interactions, we have used lymphoblastoid target cell lines preincubated with β2m. This was found to shift the equilibrium between β2m‐associated and nonassociated ‐ heavy chains in favor of the former. In parallel, there was a significant increase in NK sensitivity. The recognition of MHC class I‐deficient cell lines was not affected by β2m, arguing against a general nonspecific effect of fern on NK sensitivity. Our data indicate that protection against NK recognition correlates with target cell expression of free heavy chains (i.e.devoid of β2m) rather than with ex

ISSN:0014-2980    

DOI:10.1002/eji.1830230803

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractCoronavirus MHV‐JHM infections of rats provide useful models to study the pathogenesis of virus‐induced central nervous system disease. To analyze the role of the immune response against defined MHV‐JHM antigens, we tested the protective efficacy of vaccinia virus (VV) recombinants expressing either the nucleocapsid (N) or the spike (S) protein. A strong protection was mediated in animals by immunization with recombinant VV encoding a wild‐type S protein (VV‐SWildtype), whereas VV recombinant expressing a mutant S354CRprotein (VV‐S354CR) had no protective effect. Recombinant VV encoding N protein (VV‐N) induces a humoral and a CD4+T cell response, but did not prevent acute disease regardless of the immunization protocol. In these experiments, challenge with an otherwise lethal dose of MHV‐JHM was performed prior to the induction of virus‐neutralizing antibodies and studies with the anti‐CD8+monoclonal antibody, MRC OX8 showed that elimination of the CD8+subset of T cells abrogates the protective effect. This result indicates that CD8+T cells primed by recombinant VV expressing wild‐type S protein are a primary mechanism of immunological defense against MHV

ISSN:0014-2980    

DOI:10.1002/eji.1830230804

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractAt least two subsets of CD4+T helper cell lymphocytes termed Th1 and Th, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two Thcell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)‐1 acts onTh2 cells but not on Th1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL‐12 and exhibits a reciprocal behaviour to IL‐1. IL‐12 has several effects on Th1 cells. It can induce the proliferation of certain Th1 cells in combination with IL‐2. Synthesis of interferon (IFN)‐γ by Th1 cells can be triggered by IL‐2 plus IL‐12. In contrast to the IFN‐γ production observed after T cell receptor (TcR) CD3 stimulation of Th1 cells with lectin Concanavalin A the IFN‐γ production induced by IL‐12+IL‐2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL‐12 enhances the TcR/CD3‐induced synthesis of IFN‐γ of several Th1 clones. Finally, IL‐12 (+ IL‐2) induces homotypic cell aggregation of Th1 clones. This type of cell aggregation depends on the participation of LFA‐1 and ICAM‐1 molecules. In all activation systems with Th1 cells no effect of IL‐1 was demonstrable. In contrast, only IL‐1 but not IL‐12 served as a co‐stimulatory signal for several

ISSN:0014-2980    

DOI:10.1002/eji.1830230805

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractWe have previously found that interleukin‐4 and CD40 monoclonal antibodies (mAb) are strong potentiatiors of homotypic B cell aggregation which is dependent on LFA‐1. We show here that CD23 mAb were also able to inhibit aggregation to a similar extent as LFA‐1 antibodies. This inhibition was restricted to the MHM6 epitope of CD23 and antibodies to other epitopes [Epstein‐Barr virus (EBV) CS‐1, EBV CS‐2, EBV CS‐5 and mAb 25] or occupation of the Fc‐binding site by IgE had no or a slightly enhancing effect on aggregation. When testing two antibodies to CD21, the recently defined ligand for CD23, one of these (BU32) was found to be inhibitory whereas the other (THB5) had no effect. By combining antibodies to LFA‐1 and CD23, aggregation was often completely inhibited. These data suggest that LFA‐1/ICAM‐1 and CD23/CD21 are the major molecules involved in homotypic aggrega

ISSN:0014-2980    

DOI:10.1002/eji.1830230806

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractPeptide binding to a soluble, single‐chain Kdprotein produced by the yeast strainKluyveromyces lactis, and to Kdmolecules on Kd‐expressing cells (P815) was studied using radiolabeled Kd‐restricted peptides. The stability of the peptide‐Kdcomplexes formed was monitored in the absence and presence of unlabeled competitor peptides. Radioiodination of the Tyr anchor residue in position 2 of the peptide interferes with binding. A Kd‐biased peptide library and a modified antigenic peptide in which a second Tyr was added in positions 6 and 8, respectively, were therefore used to assay binding. Recombinant and cell‐associated Kdmolecules are very similar in the following respects: the ease with which the proteins can be loaded with labeled peptide; the spectrum of peptides selected from a peptide library; the stability of the labeled peptide‐Kdcomplex formed; and the ability to partially dissociate the class 1‐peptide complex with exogenous, unlabeled peptides. These results imply that measurements of peptide binding to soluble Kdmolecules are a reliable indicator of the peptide‐binding properties of Kdproteins on living cells. The large quantities of soluble recombinant Kdprotein currently available represent an invaluable tool not only for dissecting the molecular mechanisms of antigen presentation but also for vaccinations and the design of T cel

ISSN:0014-2980    

DOI:10.1002/eji.1830230807

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractHLA class II association with insulin‐dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult‐onset and 51 childhood‐onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for theTAP2*0201 allele [relative risk (RR)=0.3, corrected probability(pc)<0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR=3.4,pc<0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR=0.06, pc<0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB 1*0302 haplotypes predisposing effect (RR=1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed byx2analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies(p<0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to β cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM pred

ISSN:0014-2980    

DOI:10.1002/eji.1830230808

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractWe have previously shown that unlike endogenous ϰ genes, unrearranged ϰ transgenes undergo Vϰ‐Jϰ recombination in T as well as B cells of transgenic mice. To determine whether the difference in recombination specificity of the transgenic and endogenous ϰ genes is associated with differences in DNA structure, the methylation status of the endogenous genes and three unrearranged ϰ transgenes was compared. The Jϰ‐Cϰ locus of the transgenes was found to be hypomethylated in all tissues of the transgenic mice. In contrast, methylation of the endogenous ϰ genes was tissue and developmentally regulated. Hypomethylation of the endogenous Jϰ‐Cϰ region occurs only in cells of the B lineage undergoing, or having completed ϰ gene recombination. Transfection of fibroblasts from transgenic and control mice with the recombination activating genes, Rag1 and Rag2, led to a high level of rearrangement of the hypomethylated transgenic, but not the endogenous ϰ genes. These results suggest that hypomethylation defines an accessible state of the ϰ locus and that methylation/demethylation could be involved in the control of ϰ gene rearrangement during lympho

ISSN:0014-2980    

DOI:10.1002/eji.1830230809

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractThe murine antigen‐processing‐defective mutant cell line RMA‐S is leaky in the presentation of certain endogenously synthesized minor histocompatibility and viral antigens to major histocompatibility complex (MHC) class I‐restricted cytotoxic T lymphocytes (CTL). The viral antigens include influenza virus nucleoprotein, vesicular stomatitis virus (VSV) nucleocapsid and Rauscher murine leukemia virus (MuLV) antigen. Here we demonstrate Sendai virus antigen presentation by the HAM2 (murine TAP2, transporter associated with antigen presentation type 2)‐defective RMA‐S cell line and compare antigen presentation after restoration of the defect by murine TAP1/2 gene transfection. Kinetic studies revealed that RMA‐S cells required 2‐3 h longer incubation and approximately 10 times higher doses of Sendai virus to reach the same level of killing as the RMA parental line. After transfection of RMA‐S cells with the murine TAP1/2 gene, Sendai virus antigen presentation was restored to levels of the RMA wild‐type line with regard to time of virus infection and dose of virus needed for sensitizing target cells. The presentation of Sendai virus antigen in RMA‐S cells was sensitive to brefeldin A (BFA), suggesting that the presentation was mediated via the endogenous pathway. Our findings comfirmed leakiness of antigen presentation in RMA‐S cells and extended it to Sendai virus. The results underscored the role for intact expression of the TAP 1/2 molecules for efficient MHC class I‐medi

ISSN:0014-2980    

DOI:10.1002/eji.1830230810

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY

摘要:

AbstractCytotoxic T lymphocytes (CTL) recognize foreign antigens as short peptides presented by class I molecules of the major histocompatibility complex (MHC). T2 cells are profoundly defective in the presentation of endogenously synthesized antigens to CTL due to a deletion of MHC class II‐encoded genes for transporters associated with antigen presentation (TAP1/TAP2). Surprisingly, we here demonstrate that T2 cells, after infection with Sendai virus, are readily killed by H‐2Kbrestricted CD8+T cells. In contrast to classical class I‐mediated antigen presentation, the presentation of Sendai virus antigen inT2Kbcells is brefeldin A (BFA) insensitive. The present findings may suggest the presence of an alternative pathway for MHC class I‐mediated antigen presentation in T

ISSN:0014-2980    

DOI:10.1002/eji.1830230811

出版商:WILEY‐VCH Verlag GmbH    

年代:1993

数据来源: WILEY