Search

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mφ) or macrophage CSF (M-CSF)-induced human monocyte-derived Mφ (M-Mφ) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mφs, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mφs were cultured with or without bacillus Calmette–Guérin (BCG) (GM-Mφ-BCG and M-Mφ-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mφs were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mφ and M-Mφ, respectively. After stimulation with BCG, three chemokine genes ( Osteopontin ( SPP1), CXC chemokine ligand 7 ( CXCL7) and CC chemokine ligand 11 ( CCL11)) were highly expressed in M-Mφ-BCG when compared to those in GM-Mφ-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mφ with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mφs were higher than those of GM-Mφs without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mφs. [ABSTRACT FROM AUTHOR]

An autosomal recessive gene, lpr, is responsible for lymphoproliferation and autoimmunity of lpr mice, in which background genes are also known to influence the development of autoimmune disease. To define the differences in abnormally proliferating T cells between C57BL/6-lpr/lpr and MRL/Mp-lpr/lpr mice, and to try and understand the influence of background in the differing expression of autoimmune disease in both strains, we analysed the sequences of T cell antigen receptor Vβ genes expressed in the cells from the enlarged lymph nodes of C57BL/6-lpr/lpr mice. Eleven β cDNAs out of the 38 Cβ-specific cDNAs contained sequences with open reading frames from the beginning of the variable region to the expected termination codons at the end of the constant regions. Notably, 36% of the functional β-chain mRNAs expressed Vβ8.3 genes, whereas Vβ8.3 and Vβ8.2 genes were not found. These results are consistent with a relatively lower frequency of the Vβ8.1 or Vβ8.2 expressing cells in the hypertrophic lymph nodes of C57BL/6-lpr/lpr mice, detected by KJI6-133 monoclonal antibody. Interestingly, other Vβ genes expressed in these mice were completely distinct from those in MRL/Mp-lpr/lpr mice as described by Singer et al (1986), The different distribution of Vβ genes expressed in C57BL/6-lpr/lpr from that in MRL/Mp-lpr/lpr mice might be related to the differences in the genetic background and the expression of lpr gene-associated autoimmunity. [ABSTRACT FROM AUTHOR]

We previously reported that the number of TNF-α-producing cells was increased in the liver of patients with type C chronic liver disease. To understand further the pathophysiology of this change, we examined serum levels of two soluble TNF receptors, TNF-αRI (p55)and -αRII (p75), and IL-10, all of which act as TNF-α buffer, and IL-15, a novel cytokine sharing many immunological activities with IL- 2, using ELISA methods. We studied control individuals and patients with type C chronic liver disease, including asymptomatic hepatitis C virus (HCV) carriers with persistently normal serum ALT values, and those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Both types of sTNF-αR closely correlated with disease progression. Patients with LC and HCC had significantly elevated levels for sTNF-αRII compared with the other patient groups and controls. Serum IL-10 levels were significantly greater in all chronic liver disease groups than in controls. With respect to IL-15, the values were high in CH, LC and HCC compared with those of controls. Notably, HCC patients showed highest values for both IL-10 and IL-15, with significant differences from the other patient groups. Serial determinations revealed that interferon (IFN) treatment for CH patients resulted in the suppression of circulating lL-10 and IL-15 levels along with decrease in serum aminotransferase values. Both cytokines remained at decreased levels after cessation of therapy in patients who went into clinical and virological remission. On the other hand, treatment did not affect serum levels of sTNF-αRs, These findings indicate that serum levels of these molecules correlated with disease progress in chronic HCV infection, and that IL-10 and IL-15 may reflect the degree of inflammation in the liver. It is also suggested that both cytokines may be related to the development of HCC. [ABSTRACT FROM AUTHOR]

Summary: Most CD4 and CD8 T cells are restricted by conventional major histocompatibility complex (MHC) molecules and mount TCR-dependent adaptive immune responses. In contrast, MAIT, iNKT, and certain γδ TCR bearing cells are characterized by their abilities to recognize antigens presented by unconventional antigen-presenting molecules and to mount cytokine-mediated TCR-independent responses in an "innate-like" manner. In addition, several more diverse T-cell subsets have been described that in a similar manner are restricted by unconventional antigen-presenting molecules but mainly depend on their TCRs for activation. Vice versa, innate-like behaviour was reported in defined subpopulations of conventional T cells, particularly in barrier sites, showing that these two features are not necessarily linked. The abilities to recognize antigens presented by unconventional antigen-presenting molecules or to mount TCR-independent responses creates unique niches for these T cells and is linked to wide range of functional capabilities. This is especially exemplified by unconventional and innate-like T cells present at barrier sites where they are involved in pathogen defense, tissue homeostasis as well as in pathologic processes. T cells can recognize conventional (peptide-major histocompatibility complex) or unconventional ligands. In many cases, "unconventional" T cells such as MAIT cells also show innate-like features and can respond independently of their TCR. Recent data have indicated innate-like features in conventional T cells, such as the recently described TMICpopulation in gut. [ABSTRACT FROM AUTHOR]

The assessment of Toll-like receptor (TLR) agonists as candidate adjuvants for induction of effective T helper type 1 (Th1) immunity continues to rely on the use of mice. However, the genetic variation among inbred mice may influence the efficacy of adjuvants and bias a study's conclusions. Here, we evaluated the differences in cellular and humoral responses of genetically non-identical mouse strains immunized with ovalbumin (OVA) plus alum, TLR-3, TLR-4, TLR-7/8 or TLR-9 agonists. We found that all the tested TLR agonists recruited dendritic cells (DCs) and natural killer (NK) cells significantly into the lymph nodes, promoted DC-NK cross-talk and enhanced the cellular responses in B6 strain. In contrast, TLR-3 and TLR-7/8 were the only two agonists that showed the cellular adjuvanticity in the BALB/c strain. Compared with other TLR agonists, TLR-3 and TLR-7/8 were demonstrated to be the most effective adjuvants to generate interferon (IFN)-γ-producing effector NK, CD4, and CD8 T cells in B6 and BALB/c strains, respectively. We also found that compared with alum, all adjuvants induced the recruitment of B cells and production of OVA-specific immunoglobulin (Ig)G2a more effectively in both strains. In addition, the B6 strain recruited more B cells, but surprisingly produced significantly lower amounts of OVA-specific IgG2a in response to all adjuvants. However, consistent with the frequency of IFN-γ-producing effector cells observed in individual strains following immunizations, we detected more OVA-specific IgG2a in serum of B6 and BALB/c strains in response to TLR-3 and TLR-7/8, respectively. Our data suggest that genetic background should be taken into consideration when evaluating the activities of TLR agonists for the development of prophylactic and therapeutic vaccines. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories - central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future. [ABSTRACT FROM AUTHOR]

The gut immune system is usually tolerant to harmless foreign antigens such as food proteins. However, tolerance breakdown may occur and lead to food allergy. To study mechanisms underlying food allergy, animal models have been developed in mice by using cholera toxin ( CT) to break tolerance. In this study, we identify T cell receptor ( TCR)-γδ+ intraepithelial lymphocytes ( IELs) as major targets of CT to break tolerance to food allergens. TCR-γδ+ IEL-enriched cell populations isolated from mice fed with CT and transferred to naive mice hamper tolerization to the food allergen β-lactoglobulin ( BLG) in recipient mice which produce anti- BLG immunoglobulin ( Ig)G1 antibodies. Furthermore, adoptive transfer of TCR-γδ+ cells from CT-fed mice triggers the production of anti- CT IgG1 antibodies in recipient mice that were never exposed to CT, suggesting antigen-presenting cell ( APC)-like functions of TCR-γδ+ IELs. In contrast to TCR-αβ+ cells, TCR-γδ+ IELs bind and internalize CT both in vitro and in vivo. CT-activated TCR-γδ+ IELs express major histocompatibility complex ( MHC) class II molecules, CD80 and CD86 demonstrating an APC phenotype. CT-activated TCR-γδ+ IELs migrate to the lamina propria, where they produce interleukin ( IL)-10 and IL-17. These results provide in-vivo evidence for a major role of TCR-γδ+ IELs in the modulation of oral tolerance in the pathogenesis of food allergy. [ABSTRACT FROM AUTHOR]

Treatment of primary biliary cirrhosis ( PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells ( Treg) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+ T cells from the dominant negative form of transforming growth factor beta receptor type II ( dnTGF-β RII) mice to recombination-activating gene ( Rag)1-/- recipients. We then used this robust established adoptive transfer system and co-transferred CD8+ T cells from dnTGF-β RII mice with either C57 BL/6 or dnTGF-β RII forkhead box protein 3 ( FoxP3+) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57 BL/6 but not dnTGF-β RII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57 BL/6 Treg versus dnTGF-β RII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GA RP), CD73, CD101 and CD103 and a functionally significant increase in interleukin ( IL)-10 in Treg from C57 BL/6 compared to dnTGF-β RII mice. Our data reflect the therapeutic potential of wild-type CD4+ FoxP3+ Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. [ABSTRACT FROM AUTHOR]

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialized countries, this 'hygiene hypothesis' has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. In this study we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine collagen-induced arthritis ( CIA) model of rheumatoid arthritis ( RA). As its core mechanism involves targeting of interleukin ( IL)-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by T helper type 17 ( Th17) and γδ T cells, while leaving that of CD49b+ natural killer ( NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologicals, such as ' IL-17 blockers', that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential. [ABSTRACT FROM AUTHOR]

In health, mucosal inflammation is prevented by tightly regulated responses via Toll-like receptors (TLR) that interact with specific microbe associated molecular patterns. Currently, 13 TLRs have been identified. Based on the specificity of ligand recognition, TLR-2 and TLR-4 can recognize most oral commensal microorganisms. Recent identification of some soluble TLRs (sTLRs) suggests additional regulatory roles for these receptors. We report here the presence of sTLR-4 polypeptides in adult human saliva. Functionally, the salivary sTLR-4 suppressed cytokine secretion by activated macrophages. The sTLR-4 levels were elevated significantly in oral lichen planus (OLP), a chronic inflammatory condition of the oral mucosa characterized by clinical persistence. In contrast, the epithelial cells in the saliva of OLP subjects expressed significantly reduced TLR-2 and TLR-4 mRNA that correlated with fewer bacteria/salivary epithelial cells. Investigating the soluble and cellular components of saliva is useful in identifying potential biomarkers for oral mucosal lesions. [ABSTRACT FROM AUTHOR]

Renal tubular epithelial cells (TECs) respond diffusely to local infection, with the release of multiple cytokines, chemokines and other factors that are thought to orchestrate the cellular constituents of the innate immune response. We have investigated whether the Toll-like receptors TLR4 and TLR2, which are present on tubular epithelium and potentially detect a range of bacterial components, co-ordinate this inflammatory response acting through nuclear factor-kappa B (NF-κB). Primary cultures of TECs were grown from C57BL/6, C3H/HeN, C3H/HeJ, TLR2 and TLR4 knock-out mice. Cell monolayers were stimulated with lipopolysaccharide (LPS) and synthetic TLR2 and 4 agonists. The innate immune response was quantified by measurement of the cytokines tumour necrosis factor (TNF)-α and KC (IL-8 homologue) in cell supernatants by enzyme-linked immunosorbent assay. Cultured TECs grown from healthy mice produced the cytokines TNF-α and KC in response to stimulation by LPS and synthetic TLR2 and TLR4 agonists. Cells lacking the respective TLRs had a reduced response to stimulation. The TLR2- and TLR4-mediated response to stimulation was dependent on NF-κB signalling, as shown by curcumin pretreatment of TECs. Finally, apical stimulation of these TLRs elicited basal surface secretion of TNF-α and KC (as well as the reverse), consistent with the biological response in vivo. Our data highlight the potential importance of TLR-dependent mechanisms co-ordinating the innate immune response to upper urinary tract infection. [ABSTRACT FROM AUTHOR]

An author index for the March 2006 issue of "Clinical and Experimental Immunology" is presented.

Listeria monocytogenes(Listeria) are known to grow and proliferate in the liver while a splenectomy induces host resistance against aListeriainfection despite the fact that a splenectomy inhibits the Th1 response. Therefore, the mechanism by which a splenectomy helps to prevent the growth ofListeriastill remains to be elucidated. After an i.v. challenge ofListeria(1 × 106 CFU) in C57BL/6 mice,Listeriarapidly increased in the spleen but not in the liver until 48 h. However, after this initial phase,Listeriaremarkably grew in the liver. In contrast, when the mice received a splenectomy beforehand, no remarkable growth ofListeriain the liver was observed afterListeriachallenge despite the fact that serum IFN-γ and IL-12 levels at 24 h afterListeriachallenge were significantly lower than those in the sham mice. However, the liver leucocytes from mice by 6 h after infection produced a substantial amount of IFN-γ while spleen MNC did not, whereas spleen leucocytes at 24 h afterListeriachallenge did. Consistently, the IFN-γ and IL-12 levels in the tissue homogenates of the spleen were significantly lower than in those of the liver until 6 h after infection. This defective spleen Th1 response in the early phase ofListeriainfection was corrected by an IL-18 i.p. injection just after theListeriachallenge. Our findings suggest thatListeriaexploit the defective Th1 environment of the spleen in the initial phase and afterwards overcome the host defense mechanism of the liver. [ABSTRACT FROM AUTHOR]

Interleukin 15 (IL-15) is critical for the development of human and murine natural killer (NK) cells and hepatic-derived NK T cells (NKT) in mice, and for the homeostatic maintenance of NK/NKT and CD8+ memory T cells. The lymphocyte repertoire of an adult human liver includes significant populations of NK and NKT-like cells, which may arise locally from hepatic haematopoietic stem cells (HSCs). We investigated hepatic IL-15 levels and the expression of IL-2/IL-15-receptorβ-chain (IL-2/IL-15Rβ ; CD122) on mature hepatic lymphocytes and HSCs. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect secreted/intracellular IL-15 transcripts. IL-15 protein was localized using immunohistochemistry; levels were measured by enzyme-linked immunosorbent assay IL-2/IL-15Rβ expression by flow-cytometry. Normal hepatic IL-15 protein was detected at 0·43 ng/100 mg total protein (n = 11, range 0·10 ng−0·9 ng). There was a significant increase in HCV-infected tissue (1·78 ng,P < 0·005,n = 11, range 0·18–2·43 ng). The staining pattern suggests that infiltrating monocytes and tissue resident Kupffer cells are the main producers. IL-15 protein was detected in supernatants from cultured liver biopsy specimens in the absence of stimulation (mean 175·8 pg/100 mg wet tissue,n = 3), which increased significantly upon stimulation (P < 0·05, mean 231·21 pg). On average, 61% of hepatic HSCs expressed IL-2/IL-15Rβ suggesting a local lymphopoietic role. Eighty per cent of NK and 45·8% of CD56+ T cells expressed IL-2/IL-15Rβ, suggesting involvement in local CD56+ cell activation and expansion. Constitutive expression of IL-15 protein and IL-2/IL-15Rβ on hepatic lymphocytes suggests a key role in the generation and maintenance of the unique hepatic lymphoid repertoire. The significant increase observed in HCV-infected liver suggests a role for IL-15 in host antiviral responses in the liver. [ABSTRACT FROM AUTHOR]

Activated mast cells generate multiple cytokines but it is not known if these can be differentially regulated by pharmacological agents. We report here that the glucocorticoid dexamethasone (DEX) preferentially inhibited Ag induced expression of IL-4 and IL-6 mRNA relative to TNF-α mRNA in RBL-2H3 cells. Likewise, the drug more readily inhibited release of IL-4 than TNF-α protein. SB203580, an inhibitor of p38 mitogen activated protein kinase (MAPK), enhanced Ag-induced TNF-αmRNA expression without affecting IL-4 or IL-6 mRNA. At the protein level, SB203580 exerted little effect on TNF-α release but inhibited IL-4 release: notably, the ratio of TNF-α IL-4 increased mark edly with the concentration of SB203580, confirming the differential regulation of these cytokines. PD98059, an inhibitor of MAPK kinase (MEK), a component of the p44/42 MAPK pathway, partially inhibited Ag-induced expression of mRNA for all three cytokines while cyclosporin A inhibited Ag- induced IL-4 and IL-6 mRNA more readily than TNF-α mRNA. Ag activation of the cells led to phosphorylation of p38 and p44/42 MAPK but this was not influenced by DEX. In conclusion, mast cell cytokines can be differentially regulated pre-and post translationally by DEX and SB203580 but there does not appear to be a direct mechanistic link between the actions of these two drugs. [ABSTRACT FROM AUTHOR]

Intestinal epithelial cell (IEC)-derived cytokines, such as stem cell factor (SCF), interleukin (IL)-7 and IL-15 are known to be required for the development of intestinal intraepithelial lymphocytes (IELs). A newly described cytokine, IL-18, has also been shown to be produced by intestinal epithelial cells. To demonstrate the functional effects of IL-18 on human IELs, we assessed IL-18/IL-18 receptor expression in IEC/IEL and proliferation following stimulation of intestinal IELs by IL-18. IL-18 transcripts were detected both in freshly isolated human colonic epithelial cells and in various colonic epithelial cell lines. IL-18 protein was also detected by ELISA and flow cytometric analysis using antihuman IL-18-specific monoclonal antibody (MoAb). Furthermore, IELs constitutively expressed the IL-18 receptor in addition to the IL-2 and IL-7 receptors. More importantly, IL-18 augmented significant proliferative responses of IEL in combination with IL-2, IL-7 and IL-15 both in the presence and in absence of anti-CD3 MoAb. These results suggest that IL-18 might play a crucial role in the proliferation and maintenance of intestinal IELs. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Different functional effective polymorphisms for the TLR 4 gene (Asp299Gly; Thr399Ile) and for the TLR 2 gene (Arg677Trp, Arg753Gln) have recently been described that are associated with impaired lipopolysaccharide signal transduction. A total of 122 patients with chronic periodontal disease and 122 healthy unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphism of the TLR 4 gene and the Arg677Trp and Arg753Gln mutation of the TLR 2 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. The prevalence of the Asp299Gly and the Thr399Ile mutant allele was 4·1% (10/244) and 4·5% (11/244) among periodontitis patients. For the healthy controls the prevalence was 3·3% (8/244) for the Asp299Gly ( P = 0·810) and 3·7% (9/244) for the Thr399Ile mutant allele ( P = 0·819). The Arg753Gln mutant allele was found in 2·9% (7/244) of the periodontitis subjects as compared to 4·1% (10/244) in the control group ( P = 0·622). The Arg677Trp mutant allele was not found in any of the study subjects. Unlike in ulcerative colitis there was not observed an association between chronic periodontitis and the various mutations of the TLR 2 and 4 gene. [ABSTRACT FROM AUTHOR]

SUMMARY The identification of immunodominant and universal mycobacterial peptides could be applied to vaccine design and have an employment as diagnostic reagents. In this paper we have investigated the fine specificity, clonal composition and HLA class II restriction of CD4+ T cell clones specific for an immunodominant epitope spanning amino acids 91–110 of the 16-kDa protein of Mycobacterium tuberculosis . Twenty-one of the tested 28 clones had a Th1 profile, while seven clones had a Th0 profile. None of the clones had a Th2 profile. While the TCR AV gene usage of the clones was heterogeneous, a dominant TCR BV2 gene family was used by 18 of the 28 clones. The CDR3 regions of BV2+ T cell clones showed variation in lengths, but a putative common motif R-L/V-G/S-Y/W-E/D was detected in 13 of the 18 clones. Moreover, the last two to three residues of the putative CDR3 loops, encoded by conserved BJ sequences, could also play a role in peptide recognition. Antibody blockade and fine restriction analysis using HLA-DR homozygous antigen-presenting cells established that 16 of 18 BV2+ peptide-specific clones were DR restricted and two clones were DR-DQ and DR-DP restricted. Additionally, five of the 18 TCRBV2+ clones recognized peptide 91–110 in association with both parental and diverse HLA-DR molecules, indicating their promiscuous recognition pattern. The ability of peptide 91–110 to bind a wide range of HLA-DR molecules, and to stimulate a Th1-type interferon (IFN)-γ response more readily, encourage the use of this peptide as a subunit vaccine component. [ABSTRACT FROM AUTHOR]

SUMMARY Thl and Thl-inducing cytokines and T cell responses were investigated in human salmonellosis. Serum IFN-γ , IL-12 and IL-18 levels were increased significantly in patients with salmonellosis. The increase in serum IL-15 and IL-18 levels was more significant and prolonged in patients with the systemic form of salmonellosis than in those with the gastroenteric form. The serum IFN-γ level was correlated significantly with IL-12 and IL18 levels, and the IL-15 level was correlated significantly with IL-18. Upon stimulation with Salmonella in vitro , mononuclear cells from salmonellosis patients produced significantly higher amounts of IFN-γ and IL-12 compared with those from healthy controls. Anti-IL-12 moAb or anti-IL18 MoAb significantly inhibited Salmonella -induced IFN-γ production in vitro . γδ T cells expressed significantly higher levels of IFN-γ mRNA in salmonellosis patients than in healthy controls. The results suggest that Th1-inducing cytokines appear to be involved in the in vivo response against Salmonella infection, promoting IFN-γ production by αβ and γδ T cells which plays a protective role against Salmonella . [ABSTRACT FROM AUTHOR]

SUMMARY Gram-positive bacteria, which lack lipopolysaccharide (LPS), produce a septic-shock-like condition, accompanied by release of pro-inflammatory cytokines. Various components of the bacteria may be responsible for this. We stimulated a whole blood system with heat-inactivated Streptococcus pneumoniae serotype 14 (S14) bacteria, with pneumococcal S14 capsular polysaccharide (PPS S14) and with PPS S14 coated on to latex beads, to compare interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFα) production over a six hour period, to ascertain the contribution of PPS to the inflammatory response. This was compared with the response to LPS. After sonication of the bacteria, their PPS content was estimated by an enzyme-linked immunoabsorbent assay, to compare this with the concentration of free PPS needed to generate cytokine release. The whole bacteria elicited a much larger cytokine response than the equivalent amount of PPS alone, whereas the PPS-coated beads gave minimal response. The different cytokine responses to PPS and LPS suggest that there are differences in the receptors and/or signalling pathways for Gram-negative and Gram-positive bacteria. We conclude that the estimated amount of PPS in the bacteria is not enough to account for the large cytokine response we observed. Since PPS could not be shown to contribute significantly to cytokine induction, specific antibodies to PPS would not play any significant role in combating cytokine release associated with pneumococcal infection and possible septic shock. This needs to be considered in production of future vaccines. [ABSTRACT FROM AUTHOR]

SUMMARY Gamma interferon (IFNγ) plays a key role in host defense against pulmonary mycobacterial infections. A variety of lymphocyte subsets may participate in producing pulmonary IFNγ responses, but their relative contributions after mycobacterial infection have not been clearly elucidated. To address this question, C57Bl/6 female mice were infected by intrapulmonary instillation of 2·5 × 104 BCG (Mycobacterium bovis Bacillus Calmette-Guerin). Lymphocyte populations in lung interstitium were examined at different time points after the infection. BCG load in lungs peaked between 4 and 6 weeks post-infection and declined to very low levels by the 12th week of infection. Recovery of lung interstitial lymphocytes doubled by 4–6 weeks after infection and declined thereafter. Flow cytometric analysis of the lung-derived lymphocytes revealed that about 5% of the these cells made IFNγ in control mice, and this baseline IFNγ production involved T (CD3+ NK1.1- ), NK (CD3- NK1.1+ ) and NKT (CD3+ NK1.1+ ) cells. As the BCG lung infection peaked, the total number of CD3+ T cells in the lungs increased threefold at 5–6 weeks post-infection. There was a marked increase (sixfold) in the number of T cells secreting IFNγ 5–6 weeks post-infection. Some increase was also noted in the NKT cells making IFNγ, but the numbers of NK cells making IFNγ in BCG-infected lungs remained unaltered. Our results suggest that whereas NK and NKT cells contribute to baseline IFNγ secretion in control lungs, expansion in the IFNγ-producing T-cell population was essentially responsible for the augmented response seen in lungs of BCG-infected mice. [ABSTRACT FROM AUTHOR]

We previously reported that c-kit+ stem cells which give rise to extrathymic T cells are present in the liver of adult mice. Further characterization of extrathymic T cells in the liver of adult mice is conducted here. When mice with a liver shield were lethally (9.5 Gy) irradiated, all mice survived. All tested organs showed a distribution pattern of hepatic lymphocytes on day 7. The distribution pattern in the liver was characterized by an abundance of NK (CD3- IL-2Rβ+) and extrathymic T cells (CD3int IL-2Rβ+) before and after irradiation. To determine their function, post-irradiation allogeneic bone marrow transplantation (BMT) was performed in mice with or without a liver shield. Allogeneic BM cells were rejected in mice with a liver shield and specific activation of CD8+ CD3int IL-2Rβ+ cells was induced. At that time, potent cytotoxicity of liver mononuclear cells (MNC) against allogeneic thymocytes was induced. Both NK1.1+ and NK1.1- subsets of CD3int cells expanded in these mice. An in vivo elimination experiment of the subsets indicated that the NK1.1+ subset of CD3int cells (i.e. NK T cells) was much more associated with the rejection of allogeneic BM cells. However, even after the elimination of NK T cells, allogeneic BM cells were rejected. In this case, granulocytes expanded in parallel with NK1.1- subsets. Granulocytes may also be associated with the rejection of allogeneic BM cells. These results suggest that the liver is an important haematopoietic organ even in adult life. [ABSTRACT FROM AUTHOR]

A particular T cell population expressing NK cell markers, CD56 and CD57, exists in humans. Many CD56+ T and CD57+ T cells (i.e. NK T cells) exist in the liver and increase in number in the blood with ageing. They may be a human counterpart of extrathymic T cells, similar to NK1.1+ CD3int cells seen in mice. We investigate here the existence of such NK T cells in human cord blood and the in vitro expansion of these cells by the stimulation of human recombinant IL-2 (rIL-2). There were very small populations (< 1.0%) of CD56+ T cells, CD57+ T cells, and γδ T cells in cord blood. However, all of these populations increased in number after birth and with ageing. When lymphocytes in cord blood were cultured with rIL-2 (100 U/ml) for 14 days, CD56+ T cells expanded up to 25% of T cells. CD57+ T cells were never expanded by these in vitro cultures. The expansion of γδ T cells (mainly Vγ9- non-adult type) also occurred in the in vitro culture. A considerable proportion of CD56+ T cells was found to use Vα24 (i.e. equivalent to invariant Vα14 chain used by murine NK T cells) for TCR αβ. These results suggest that neonatal blood contains only a few NK T cells but CD56+ NK T cells and γδ T cells are able to expand in vitro. [ABSTRACT FROM AUTHOR]

By using a flow cytometric technique which allows direct identification of proliferating cells within mixed cell populations, we have previously described that soluble extracts obtained from Mycobacterium tuberculosis or M. avium represent strong stimuli for human γδ+ T cells. In the present study, we demonstrate that the protocol used for the preparation of M. tuberculosis soluble extracts may have an impact on their γδ+ T cell stimulatory capacity. In agreement with our previous data, soluble extracts prepared from bacteria killed at 85°C and directly disrupted by prolonged sonication (TBe), elicited a strong proliferation of γδ+ T cells after 6–7 days of stimulation. In contrast, when soluble extracts were obtained from bacteria autoclaved (121°C, 25 min) and then washed by centrifugation, a predominant proportion of CD4+ αβ+ T cells was achieved in the responding population. The stimulatory activity for γδ+ T cells was recovered in the supernatant of the autoclaved bacteria, indicating that autoclaving of M. tuberculosis bacilli releases an antigen(s) into the supernatant which stimulates human γδ+ T cells. While protease digestion of TBe only partially reduced its stimulatory capacity on γδ+ T cells, the stimulatory component(s) released into the supernatant after autoclavation of bacilli was found to be sensitive to protease digestion. Interestingly, in contrast to the preponderant proportion of γδ+ T cells induced in the responding population by unfractionated TBe, when the extract was fractionated by fast performance liquid chromatography (FPLC), most of the fractions exhibited a strong stimulatory capacity on CD4+ αβ+ T cells only. The γδ+ T cell stimulatory activity was confined to the low molecular weight... [ABSTRACT FROM AUTHOR]

The article presents the list of the authors who contributed to the articles published in this journal "Clinical & Experimental Immunology." The names of some of the authors are: T. Abe, M.A. Addessi, D. Caccavo, V. Caldar, S.R. Holdsworth, T. Hayakawa, A.J. Hanse, G. Luccarelli, Y. Kaneko, K. Kameda, J. Kadota, S. Lightman, H. Link, H. Kajitani, A. Karlson, P. Kern, S. Kinoshita, K. Kikuchi, H. Koizumi, A. Matsuura, S. Makha, T. Lund, M.W. Madsen, M. Ludgate, Y.R. Mahida, G. Milton, A.M. Mazzone and J. Mehrotra.

Increased density of γ/δ T cell receptor (TCR)+ intraepithelial lymphocytes is the only characteristic in the jejunum of patients with coeliac disease and dermatitis herpetiformis which is not normalized on a gluten-free diet. We explored the age-dependent changes in intraepithelial γ/δ and α/β TCR+ cells from 137 biopsies from patients with coeliac disease and dermatitis herpetiformis and from controls. Biopsy specimens from 100 patients with coeliac disease and dermatitis herpetiformis and from 37 controls were studied with an immunohistochemical method using MoAbs to T cell receptors and peroxidase staining. An increase in the density of intraepithelial γ/δ T cells above the mean +2 s.d. of the density in controls was present in 97 of 100 specimens from patients with coeliac disease and dermatitis herpetiformis. The density of γ/δ+ cells of patients with coeliac disease and dermatitis herpetiformis on a normal gluten-containing diet showed a positive correlation with age (r=0.45, P<0.0001). In controls, the density of γ/δ+ cells remained low throughout the age-range studies, from age 0.6-57 years. In controls, α/β+ cells increased with age (r = 0.57. P<0.001). The increase in density of intraepithelial lymphocytes with age is in agreement with their thymus-independent character and local proliferation. [ABSTRACT FROM AUTHOR]

IL-4 plays a key role in the contact sensitivity skin reaction. This has several implications. First, the view that contact sensitivity (CS) is only mediated by cells with a Th1 profile of cytokine secretion needs modification, in the light of the essential role of IL-4 at the effector stage. Second, the concept of a single cell involved in the systemic transfer of CS is no longer tenable, as it is known that both αβ and γδ cells are required. Studies with the cell lines (which contain both αβ and a few γ'δ cells) suggest that this double requirement may involve the action of IL-4 on γδ cells, which bear receptors for IL-4. Finally, the view that T cell lines only transfer CS when injected locally, but not when injected intravenously (systemic transfer), is correct but incomplete, as T cell lines actually give systemic transfer of CS, providing the cell line or the recipient is treated with IL-4. [ABSTRACT FROM AUTHOR]

The age-related changes in proportion of various subsets within lymphocytes were investigated in cord blood and peripheral blood from healthy children and adults. The percentages of T and B cells did not show age-related changes, whereas natural killer (NK) cells increased significantly with age. Within lymphocytes or the CD3+ T cell population the proportion of CD45RAbright+ lymphocytes decreased and that of CD45RO+ cells increased, while that of CD45RAdim+ cells showed no age-related change. Within lymphocytes, the percentage of CD45RAbright+ CD4+ cells decreased, together with a decline of that of CD4+ cells. The proportions of CD45RAbright+ CD8+ cells and S6F1bright+ CD8+ cells increased with age and the age-dependent increase of the proportion of CD8+ cells seems to be mainly attributable lo the increases in these subsets. The CD45RAdim+ CD4+ and CD45RAdim+ CD8+ cells co-expressing CD45RO at a low level nevertheless showed no age-related changes. In γδ T cells, both δTCSI+ and δTCSl- T cells increased with age, but the δTCSl- γδ T cells increased more than the δTCSl+ subset. Among lymphocytes, the percentages of CD20+, CD21+ and CD22+ cells remained similar, with no age-related changes, but the proportion of CD5+ cells within lymphocytes or B cells decreased. The proportions of CD16+ NK cells among lymphocytes increased with age, and this change was attributable to the increase of CD56+ cells. [ABSTRACT FROM AUTHOR]

Fresh (uncultured) TIL from 12 untreated patients with primary renal cell carcinoma were prepared from tumour specimens by enzymatic digestion, and were characterized by immunofluorescence using MoAbs recognizing leucocyte differentiation antigens or particular Vα or Vβ segments of the T cell receptor (TCR), These fresh TIL comprised CD3+ (20-84%); CD4+ (3- 15%); CD8+ (13-35%); αβTCR+ (20 50%); 7<5TCR+ (3-17%); CD16' (1-18%) and CD56+ (3-10%) cells. Significant proportions of Vα2+, Vβ5.1+ and Vβ6+ cells were found in TIL of certain patients with renal cell carcinoma, suggesting that they comprised oligoclonal T cells. T cell lines were developed in low concentrations of rIL-2 (200 U/ml) from TIL from 11 patients with renal cell carcinoma, and were characterized by immunofluorescence and cell-mediated cytotoxicity. These T cell lines consisted primarily of CD3+ (51-94%); CD4+ (1 80%); CD8+ (0-84%); αβTCR+ (65-87%); γδTCR+ (0-25%); CD16+ (0- 16%) and CD56+ (2-57%) cells. These T cell lines exhibited non-specific cytotoxicity against autologous and allogeneic renal tumour cells, with the exception of one T cell line that exhibited preferential cytotoxiciiy against autologous renal tumour cells. These results suggest that fresh TIL from patients with renal cell carcinoma contain significant proportions of oligoclonal T cells that may have accumulated at the tumour site as a result of a clonal expansion. [ABSTRACT FROM AUTHOR]

When MRL/lpr (H-2k) spleen cells were intraperitoneally injected into C.B-17-scid/scid (severe combined immunodeficient (SCID)) (H-2d) mice, the SCID (SCID-MRL/lpr) mice manifested a severe wasting syndrome with weight loss, splenic atrophy, and lymphoid cell infiltration in the liver and lung, as seen in lpr-GVHD. In contrast, MRL/+ spleen cell-injected SCID (SCID-MRL/+) mice did not show lpr-GVHD. The spleens of SCID-MRL/lpr mice showed progressive increases in donor CD4+ and CD8+ T cells from 4 to 12 weeks after injection and a decrease in B cells at 12 weeks. SCID-MRL/+ mice showed a stable engraftment of CD4+ and CD8+ T cells and a progressive increase in B cells. Analyses of T cell receptor (TCR) repertoires (Vβ6, Vβ8.1,2 and Vβ11) revealed that the Vβ8.1,2+ T cells were found more frequently in SCID-MRL/lpr mice than in SCID-MRL/+ mice. When SCID-MRL/lpr mice were treated with intraperitoneal injection of an anti-Vβ8.1,2 (KJ16) MoAb, Vβ8.1,2+ T cells were markedly depleted, and the severity of lpr-GVHD was attenuated at 4 and 8 weeks after treatment, in contrast to normal rat IgG-injected SCID-MRL/lpr mice. However, the KJ16 MoAb-treated SCID-MRL/lpr mice suffered from severe lpr-GVHD 12 weeks after treatment, although Vβ8.1,2+ T cells were still maintained at a low level. These findings suggest that V β8.1,2+ T cells are a major T cell population that mediates lpr-GVHD in the early stage of lpr-GVHD, but that in the later stage, the other T cell populations may proliferate naturally or in accordance with the depletion of V β8.1,2+ T cells, and contribute to the development of lpr-GVHD. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes belongs to the group of intracellular bacteria, which means that they reside and multiply within host cells. The protective immunity against such an infection is mediated by cellular immune mechanisms. Whereas the CD8+ T cell population plays a major role therein, the CD4+ T cells are held to be of minor importance in this defence system. Consequently, one can understand that immune suppression with FK 506 which acts primarily on this latter T cell subset, does not interfere with protective immunity of mice infected with L. monocytogenes. We have demonstrated that the drug blocks neither curing of primary infection, nor formation of granulomas, nor induction of cell populations capable of mediating adoptive transfer of immunity, nor expression of pre-existing immunity. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) is a common disease in the elderly. It is characterized by focal inflammatory lesions dominated by T lymphocytes and macrophages. The etiology of GCA is, however, still unknown. The aim of the present study was to determine whether lesional T cells represent clonal proliferations, and to characterize adhesion receptors that could be important for recruitment of T cells and antigen receptors involved in their activation. Temporal artery biopsies were obtained from 13 patients presenting with clinical signs of GCA. Immunohistochemistry was used to characterize cell surface receptors on CD3+ T cells in situ in the lesions of eight patients with biopsy-verified GCA. The overwhelming majority of T cells in GCA lesions expressed the TCRαβ receptors. In sections from three of eight patients, a small proportion of cells expressing TCRγδ was also seen. Almost all T cells expressed the integrin receptors, LFA-1 and VLA-1, as determined by double-staining. To characterize the clonal composition of the lesional T cell population, cells were isolated by collagenase digestion of two lesions and T cells cloned by limiting dilution in the presence of mitogenie antibodies, TL-2 and autologous feeder cells. Rearrangements of the T cell receptor (TCR) genes of the clones were analysed by Southern hybridization using probes for TCRγ and β genes. T cell clones established from GCA lesions exhibited heterogeneous rearrangement patterns, indicating a polyclonal origin of the cells. We conclude that GCA lesions contain T lymphocytes that are of polyclonal origin and express integrin-type adhesion receptors. This supports the hypothesis that GCA involves an inflammatory response during which polycional T cells adhere to arterial tissue components and accumulate in the developing lesions. [ABSTRACT FROM AUTHOR]

The article provides information about recognizing T cell receptor (TCR) restriction in autoreactive T cell in human autoimmunity. The wide repertoire is advantageous in defending the individual against a large variety of external noxae, but the random nature of the process could also result in T cells recognizing self-peptides, which might initiate an autoimmune response. The article informs that with regard to the possibility of identifying a restricted TCR usage in human autoimmunity, the results have been quite disappointing. Most studies regarding the subject have employed polymerase chain reaction analysis of mRNA extracted from the total T cell population obtained from a variety of affected tissues.

Human umbilical vascular endothelial cells (HUVEC) express HLA class II molecules upon stimulation with recombinant human interferon-gamma (IFN-γ). Staphylococcal enterotoxin (SE) A (SEA)-binding assay using [125]-SEA showed the presence of specific SEA binding in HUVEC stimulated with IFN-γ but not in unstimulated HUVEC, Levels of HLA class 11 expression and SEA binding increased as the IFN-γ concentration and the period of stimulation were increased. Binding of [125I]-SEA to the IFN-γ-stimulated HUVEC was reduced markedly by an anti-DR/DP MoAb. T cells produced IL-2 upon stimulation with a group of SEs (SEA, SEB, SEC, SED and SEE) in the presence HUVEC stimulated with IFN-γ but not in the presence of control HUVEC. The level of accessory cell activity in the IFN-γ-stimulated HUVEC was related lo the level of HLA class II expression and SEA-binding activity. Antibodies to HLA class II molecules almost completely inhibited the response. These results indicate that HLA class II molecules are directly involved in the acquisition of these activities in HUVEC. [ABSTRACT FROM AUTHOR]

It has been suggested that T lymphocytes expressing γλ T cell receptrs (TCR) could play an important role in the defence of epithelia against infection and neoplastic transformation, but the potential for γλ T lymphocytes to serve these functions in human respiratory epithelium has received little attention. In this study, we used immunohistochemical techniques and specific monoclonal antibodies to characterize the number and distribution of T lymphocytes expressing αβ and γλ TCR in normal human lung and in lung carcinomas. T lymphocytes present in normal bronchi and alveolar parenchyma were predominantly of the αβ TCR phenotype, whereas γλ T lymphocytes represented only 1.1 ± 0.7% and 1.3 ±0.5% of total CD3+ lymphocytes respectively. An important lymphocytic infiltration was noted in the stroma of all primary lung carcinomas examined, and some T lymphocytes were also present infiltrating between tumour cells. These T lymphocytes were almost entirely αβ T cells and only rare γλ T cells were found, regardless of the histologic type of carcinoma (0.8±0.1 % of CD3+ T cells). This study demonstrates that T cells present in normal bronchi and lung parenehyma and those infiltrating primary lung carcinomas express predominantly αβ TCR. These findings do not support the conclusion that γλ T lymphocytes play an important role cither in the defence of human lung epithelia or in immune responses directed against primary lung carcinomas. [ABSTRACT FROM AUTHOR]

This paper describes the spontaneous occurrence of an autoimmune uveoretinitis in nude (nu/nu) mice reconstituted when 4 weeks old by the grafting of rat embryonic thymus. The uveoretinitis was characterized histologically by progressive loss of the photoreceptor layer, observed in 4.0, 17.6, 42.9% and 71.4% of such mice at 3, 5, 7 and 12 months of age, respectively. Mice with uveoretinitis were shown to have serum IgG antibody reactive by indirect immunofluorescence with retinal photoreceptors, and with interphotoreceptor retinoid-binding protein (IRBP), but not retinal S-antigen, by immunoblotting and ELISA. A uveoretinitis could be adoptively transferred to syngeneic ungrafted nude mice by splenic CD4+ T cells from diseased animals. This is the first experimental model of a (T cell mediated) autoimmune uveoretinitis which develops spontaneously and which is not dependent upon deliberate sensitization with retinal antigens and adjuvants. [ABSTRACT FROM AUTHOR]

The dominant presence of specific T-cell populations in the rheumatoid joint as detected by Southern blot analysis of T cell receptor (TCR) gene rearrangements would indicate local antigen recognition and T cell proliferation. We therefore studied TCR β chain gene rearrangements using a Cβ2 probe in paired samples of T cell populations from synovial tissue and peripheral blood (n = 6) as well as synovial fluid (n = 16) and peripheral blood (n = 18) of patients with rheumatoid arthritis (RA). Peripheral blood mononuclear cells from healthy donors (n = 7) served as a control. T cells were studied directly after isolation or after non-specific expansion with OKT3 monoclonal antibody (MoAb) and T cell growth factor (TCGF). DNA samples were digested with EcoRI and HindIII to detect rearrangements to Cβ1 and Cβ2, respectively. Extra bands were detected in all EcoRI-digested DNA samples prepared from both freshly isolated and non-specifically expanded T cell populations of patients and healthy donors, possibly representing `common' (V-) D-J rearrangements. Dominant rearrangements were found in only two out of 16 synovial fluid T cell populations (one freshly isolated and one expanded) and not in peripheral blood or synovial tissue derived T cell populations. No extra bands were detected in HindIII-digested DNA samples. To investigate the effect of in vitro culture techniques on rearrangement patterns we studied DNA samples prepared from synovial tissue T cells obtained both by outgrowth from tissue with TCGF or by enzyme digestion and subsequent expansion either with TCGF or with OKT3 MoAb and TCGF. Whereas the latter T cell population yielded 'common' rearrangements, the former T cell populations yielded different dominant rearrangements. These data indicate that oligoclonality of the T cell populations in synovial tissue and synovial fluid of patients with RA is a rare event. The data also show the influence of in vitro culture techniques on the result of TCR gene rearrangement analysis. [ABSTRACT FROM AUTHOR]

The CD3-T cell receptor (TcR) complex is central to the immune response. Upon binding by specific ligands, internalized CD3-TcR molecules increase, and either T cell response or unresponsiveness may ensue depending on the triggering conditions. Using semi-solid agar culture, we have shown previously that quiescent CD4 but not CD8 lymphocytes generate clonal colonies under phytohaemagglutinin stimulation. Here we have demonstrated that the agar induces selective CD3 TcR modulation in the CD8 and not in the CD4 subset, CD8 lymphocytes preactivated in liquid culture and recultured in agar with exogenous recombinant interleukin-2 generate colonies with a modulated CD3 TcR surface expression. The peptides composing the CD3-TcR complex are synthesized in CD8 colonies as well as in CD4; however, the CD3 gamma chain is phosphorylated at a higher level in CD8 colonies, A component of the agar polymer, absent in agarose, appears to be the ligand that induces differential CD3-TcR modulation in the CD8 subset. In contrast to agar culture, CD8 colonies can be derived from quiescent CD8 lymphocytes in agarose. These CD8 colonies express unmodulated CD-TcR, CD3 TcR modulation with anti-CD3 monoclonal antibody prior to culturing in agarose inhibits the colony formation. We conclude that given triggering conditions can result in both CD3-TcR modulation and inhibition of the proliferative response selectively in the CD8 lymphocyte subset and not in the CD4. [ABSTRACT FROM AUTHOR]

This article presents a list of authors whose articles have been published in the journal "Clinical & Experimental Immunology." Some of the authors mentioned in the list are T. Akabane, G. Akoun, R. Ardaillou, C. Danese, V.J. Desmet, D.P. Duckett, G. Eder, P. Emery, A. Lehuen, H.C. Lestra, H.C. Lestra, S. Nakamura, K. Oberg, T. Olsson, M.B. Pepys, I. Petterson, J.J. Pocidalo, J. Rautonen, S. Raziuddin, B.E. Roberts, S. Sacchetti, H. Schmitz, P.E. Slater, S.R. Wang, M. Yagame, K. Yamaguchi, E. Savilahti, G. Serre.

We studied the T cell antigen receptor (TcR) constant beta chain genes on LILA typed Japanese patients with ulcerative colitis (UC). A TcR constant beta EcoRI 6.0-kb fragment was present in all Japanese UC patients (n= 17) but completely absent in the controls (n=35) (χ = 47.6, P<0.001). The frequency of HLA-DR2 antigen was significantly higher in UC patients (85% versus 28% in controls, P < 0.001). Furthermore, H LA-DQwl antigen was also increased in UC patients (96% versus 60% in controls, P<0.001), However, HLA-DR4 antigen was significantly decreased in UC patients (12% versus 37%, P=0.02). HLA-DR1 antigen was not found in UC patients and was present in only 15% of the controls. These results suggest that TcR beta chain and HLA-DQwl antigen may be important in the pathogenesis of Japanese UC. [ABSTRACT FROM AUTHOR]

The immunomodulating effects of two locally administered cytostatic drugs, the active cyclophosphamide- derivative Z 7557 and the plant alkaloid VP-16, were compared with the effects of systemically administered cyclophosphamide and several established adjuvants: Freund's complete adjuvant, dextran sulphate, and dimethyl dioctadecyl ammonium bromide (DDA). All agents tested promoted the development of delayed-type hypersensitivity (DTH) to keyhole limpet haemocyanin (KLH) in mice. Locally administered cytostatic drugs were the most effective immunostimulatory compounds, whereas DDA was the least toxic agent tested. In order to increase the effectiveness and/ or reduce the toxicity of these agents we tested the efficacy of combinations of cytostatic drugs and DDA to enhance DTH. The results show that DDA and suboptimal amounts of locally administered cytostatic drugs act synergistically on DTH. [ABSTRACT FROM AUTHOR]

This article presents author index. Some of the authors are, T. Asano, R. Badu, J.C. Bakker, K. Barett, R. Barett, S. Benuzzi, P. H. Black, A.E. Bolton, T.L. Bowlin, K.A. Brown, G. Buchan, M. Bull, J. N. Buler, G. Cambridge, and others.

In acute infectious mononucleosis large numbers of atypical lymphocytes proliferate in response lo B cells infected with Epstein-Barr virus, generally resulting in a self-limited illness, Although both T-cells and NK cells are known to be involved. The precise origin of the large granular lymphocytes in this disorder is incompletely understood. Using two-colour immunofluoroscent flow cytometry, we sequentially examined the phenotype of selected T cell and NK cell subsets from nine patients with infectious mononucleosis. In parallel, we determined whether these lymphocytes utilized a restricted repertoire of the T cell receptor gene and also measured their NK activity. Our results show that in acute infectious mononucleosis there was a greater than three-fold increase in T lymphocytes with the phenotype CD2+,CD3+,CD8+ and DR+. A modest increase in Lcu7(HNK1) + and CD4+ T cells was also seen. In addition, there was three-fold increase in cells co-expressing CD3- and CD16+, the phenotype reported to represent most NK cells. In spite of this latter finding, however, a marked decrease in NK function was found at the time of diagnosis, gradually returning to normal by day 28. Finally, Southern blot analysis of DNA from patient lymphocytes showed polyclonal rearrangements of the T cell receptor beta chain gene. These studies indicate that the proliferation of activated suppressor/cytotoxic T lymphocytes in acute infectious mononucleosis is polyclonal and is associated with transient depression of NK function. [ABSTRACT FROM AUTHOR]

In essential mixed, type IL cryoglobulinaemia (EMC) monoclonal autoantibodies with rheumatoid factor activity are synthesized at an accelerated rate by non-malignant B lymphocytes. In order to determine if the high cryoglobulin production rate is related to a clonal B cell expansion, ceil surface markers of peripheral blood lymphocytes (PBL) were analysed by flow cytometry and the rearrangement of immunoglobulin (Ig) genes was investigated by Southern blot analysis of DNA extracted from the PBL of 12 EMC patients. Clonal expansion of B cells could be detected using DNA probes specifie for the cκ, c-mu. and JH genes in four out of 12 patients, two of whom also showed specific expansions of mu heavy and kappa light chain bearing cells using flow cytometry. The rearrangement of the c-mye locus was also noted in one of the patients with detectable Ig gene rearrangements. Demonstration of clonal B cell expansions in EMC patients shows that the clonal type of Ig gene rearrangements arc not unique markers of malignant lymphomas but may also occur in autoimmune lymphoproliferative disorders. Since malignant B cell lymphomas can develop in a small number of EMC cases, the follow-up of these patients should be pursued indefinitely. [ABSTRACT FROM AUTHOR]

This article discusses the potential role of superantigens in inflammatory bowel disease. Superantigens are the protein products of a number of bacteria and viruses. Their name derives from their ability to stimulate large numbers of T cells compared with that seen with conventional antigens. Superantigens may also be retrovirally encoded. The protein product of the ORF gene of the mouse mammary tumour virus and the gag gene-encoded p30 antigen of the LP-BM5 variant strain of the murine leukaemia virus are good examples.