In both systems, considerably higher cytotoxicity was elicited against respective B7-H3-transfected tumour cells (Fig. 3b), suggesting that B7-H3 on tumour cells augments the cytolytic effector function of antigen-specific CD8+ T cells in vivo during this website the effector phase. We obtained five types of in vivo transplantable tumour cells including mastocytoma (P815), T lymphoma (EL4), plasmacytoma (J558L), squamous

cell carcinoma (SCCVII) and melanoma (B16) to investigate the effects of B7-H3 transduction on anti-tumour immunity. All tumour cells expressed endogenous cell surface B7-H3, although the levels were low (Fig. S1). Four tumours, but not the B16 melanoma, expressed substantial levels of MHC class I, but none of the tumours expressed endogenous CD80 or CD86. P815 and J558L cells expressed CD54. We established respective B7-H3 transfectants that stably expressed B7-H3 at high levels. B7-H3 transduction did not affect other cell-surface expression including MHC class

I, CD54, CD80 and CD86 (Fig. S1). All B7-H3-transduced tumour cell lines showed comparable growth in culture and the buy Dorsomorphin addition of anti-B7-H3 mAb did not clearly affect their growth (data not shown). Five B7-H3-transduced tumours and their respective parental tumours were injected subcutaneously into syngeneic mice, and tumour growth was monitored to examine tumorigenicity. All of the parental tumours grew progressively, whereas the growth of B7-H3-transduced

tumours was efficiently inhibited (Fig. 4). The inoculation of parental or B7-H3-transduced P815 cells into immunodeficient BALB/c nude mice showed a comparable growth curve (Fig. 4f), suggesting T-cell-dependent action in the rejection of B7-H3/P815 tumours. These results indicate that B7-H3 transduction into tumours markedly reduced tumorigenicity. To examine the requirements of CD8+ and G protein-coupled receptor kinase CD4+ T cells for tumour-associated B7-H3-induced anti-tumour immunity, we pre-treated with anti-CD4, anti-CD8 mAb, or a mixture of both mAbs to deplete CD4+, CD8+, or both T cells, and then B7-H3/SCCVII cells were inoculated. Depletion of either CD4+ or CD8+ T cells slightly enhanced mean tumour volume and four out of five mice failed to reject the tumours from CD4-depleted mice, whereas all of the mice failed to reject the tumours from CD8-depleted mice (Fig. 5a). The depletion of both CD4+ and CD8+ T cells dramatically promoted tumour growth, resulting in a reversal of the B7-H3 transduction effects. These results suggest that both CD4+ and CD8+ T cells are required, and that CD8+ T cells alone are insufficient for eradicating B7-H3/SCCVII tumours. We have recently reported that TLT-2 is a counter-receptor for B7-H3.

The mock-immunized group that received an AJ challenge were reduced to two mice in the group because of a technical error during challenge. The resulting blood-stage infections were followed by microscopic examination of Giemsa’s solution-stained thin blood smears taken daily using venous blood from the tail. In order to determine the day at which parasites first became detectable in the blood, at least 10 000 red blood cells were examined per smear. For the generation of sporozoites, Anopheles stephensi mosquitoes were allowed to feed on anaesthetized mice that had been inoculated with 1 × 106 iRBCs IP 6 days

previously. Prior to feeding, mouse blood was checked for this website the presence of gametocytes, and their viability assessed by the observation of exflagellation of microgametocytes in fresh blood CP-690550 mw preparations. Seven to 10 days post-feed, mosquito mid-guts

were dissected and the presence of oocysts confirmed. Sixteen days post-feed, mosquito salivary glands were dissected into a 50 : 50 solution of FCS and Ringer’s solution, crushed in a glass and Teflon tissue homogeniser, and the numbers of sporozoites in the homogenate assessed by counting with a haemocytometer. In order to assess sporozoite viability, only those sporozoites displaying circular gliding motility were considered viable. There were no discernable differences in the viability of CB and AJ sporozoites, and sporozoites of both strains were handled in exactly

the same manner prior to immunization and challenge inoculation. All mice were kept on 0·05% para-aminobenzoic acid (PABA)-supplemented water ad libitum and were housed at 21°C on a 12 h-light–dark cycle. Anopheles stephensi mosquitoes were fed with 0·05% PABA-supplemented 10% glucose solution and were housed at 27°C and 70% humidity on a 12-h light–dark cycle. We used R version 2·7·0; The R Foundation for Statistical Computing; http://www.R-project.org) for data analysis. To analyse patterns of parasitaemia during infections, we used mixed effects models because, by treating each infection as a ‘random’ effect, we can account for repeated measures from each infection and overcome pseudoreplication problems associated with such data. These 4-Aminobutyrate aminotransferase models were fitted with Poisson error distributions and minimized following stepwise deletion of the least significant term, using log-likelihood ratio tests to evaluate the change in model deviance, until only significant terms remained. We present F-ratios for fixed effects remaining in minimal models. Mann–Whitney tests were used to compare patency data. Cumulative, summary data were analysed with linear models, using anova (F ratios) to evaluate significance of terms. The days on which parasites became detectable by microscopy (patent) in the blood of mice subjected to various immunization and challenge regimens are shown in Table 1.

4A and Table 1). Spleen and

lymph nodes of IgM or JH KO rats showed barely detectable IgM or IgD positive cells (Fig. 4A, Table 1 and Supporting Information Data 4). The total number of cells in the spleen and lymph nodes of IgM or JH KO rats were drastically decreased versus WT rats (Table 1). IgM+ and CD45R+cells in the spleen of IgM or JH KO rats were drastically decreased versus WT rats (IgM+: 0.7 and 2.28%, respectively; CD45R+: 1.6 and 4.3%, respectively) (Table 1). FACS analysis showed the presence of a small population of CD45R+IgM− cells in spleen (Fig. 4A, Table 1). Immunohistology revealed their location mainly in the spleen red pulps IWR-1 (data not shown). Using several markers, we confirmed that the phenotype of CD45R+ cells in IgM KO rats corresponded to the previously described phenoype of rat pDC 18 (data not shown). In lymph nodes, absolute numbers

of IgM+ or CD45R+ cells were greatly reduced in IgM or JH KO rats versus WT controls (∼4 and ∼4.5%, respectively) (Table 1). In BM of IgM or JH KO rats, we observed no immature or mature B cells and greatly reduced proportion of pro–pre B cells Ivacaftor datasheet (IgM− CD45Rlow) (Fig. 4A). The absolute number of mononuclear cells was significantly reduced in IgM and JH KO versus WT rats (42.2 and 56.7%, respectively) (Table 1) and numbers of pro–pre B cells (IgM− CD45Rlow) in IgM, JH KO and WT were 12.8 and 22.4%, respectively, versus WT (Table 1). T cells in spleen, as defined by double staining using anti-TCRαβ and anti-CD4 or anti-CD8 Ab, showed an increased proportion Meloxicam of TCRαβ+ cells compared with WT rats (∼85% in IgM and JH KO rats versus ∼40% in WT animals), both of the CD4+ and CD8+ subtypes (Fig. 4B). Despite this increase, the total numbers of spleen cells in IgM and JH KO rats were only 13.6 and 16.6%, respectively, compared with WT spleen cells and thus the total numbers of TCRαβ+ cells in IgM and JH KO rats were 30 and 33.7%, respectively, versus WT (p=<0.05 for both IgM or JH KO versus WT) (Table 1). Despite the fact that cell numbers in the lymph nodes were considerably decreased in IgM or JH KO versus WT rats (43

and 39%, respectively), T cells were not significantly reduced (Table 1) due to a significantly increased proportion of TCRαβ+ cells (∼95% for both KO versus ∼78%, respectively) with the CD4+ or CD8+ surface marker (Supporting Information Data 2). In BM, the proportion of TCR+ cells was increased in IgM or JH KO versus WT rats (both ∼35 versus ∼10%, respectively) in both compartments, TCR+CD4+ and TCR+CD8+ (Supporting Information Data 2). The total number of T cells was also significantly increased in IgM or JH KO versus WT (275 and 201%, respectively) (Table 1). In thymus of IgM or J KO rats, the proportion of TCR+, TCR+CD4+ and TCR+CD8+ cells (Supporting Information Data 3) as well as the total number of T cells (Table 1) were comparable.

Thus, both complement-dependent and complement-independent apoptotic cell clearance is immune inhibitory. Since complement opsonization may involve late clearance 14, or clearance in specific circumstances, we used a strictly complement-dependent apoptotic cell clearance model in this study, in order to further understand the distinct β2-integrin-restricted inflammatory inhibition in apoptotic cell clearance. To study the pro- or anti-inflammatory response of complement-dependent

apoptotic cell clearance, we used our previously described system 12, 15. Briefly, apoptotic murine thymocytes are bound to human monocyte-derived macrophages in an iC3b-CR3-dependent interaction. This is a unique system, where complement-dependent clearance of apoptotic cells is seen in >90% of apoptotic cell-phagocyte interactions. As shown in Fig. 1A, complement factors were required for apoptotic thymocyte binding GW-572016 supplier or engulfment (i.e. interaction index) by human macrophages. In the presence of fresh serum, the interaction index was 389±45, but a 90% decrease to 37±16 (p<0.0001) was documented upon heat inactivation, and an 86% decrease

to 55±18 (p<0.0001) was shown with C3-depleted serum. This decrease was reversed by addition of C3, but not by adding the nonrelevant C9. The same model was applied to uptake by immature DC (iDC), where a complement-specific interaction was Stem Cell Compound Library mouse obtained (not shown). In order to determine whether the interacting cells are engulfed in this system, we washed all nonadherent cells after 1 h of interaction,

and then incubated interacting macrophages for 12 h. As shown in Fig. 1B, the interaction index was still more or less the same, even 12 h after interaction, with no evidence of engulfment. IKBKE This might indicate that adhered cells were not completely engulfed and digested. Using transfection of CD11b/CD18 in CHO cells, we have previously shown that macrophage interaction with iC3b-opsonized thymocytes is CD11b/CD18- and CD11c/CD18-dependent 12. For comparison we used our previously described noncomplement interaction system 5, in which most interacting apoptotic cells had disappeared almost completely by 12 h (data not shown). Thus, this model allows highly specific complement-dependent apoptotic cell−phagocyte interaction. Complement, activated on the surface of apoptotic thymocytes, forms iC3b that allows CD11b/CD18-, CD11c/CD18-, and possibly additional unknown iC3b receptor-dependent interactions. However, it is not completely clear whether these interactions by themselves are sufficient for engulfment, or only for adhesion or tethering. We next wanted to verify whether interaction with CD11b/CD18 and CD11c/CD18 generates a distinct immune response following interaction with apoptotic cells. IL-1β and IL-6 were used as the prototype cytokines, indicating an inflammatory response of macrophages, while IL-10 and TGF-β were used as indicators of an anti-inflammatory response 2, 4.

The authors declare no conflicts of interest. “
“It has been proposed that mannose-binding Metformin order lectin (MBL) levels may impact

upon host susceptibility to tuberculosis (TB) infection; however, evidence to date has been conflicting. We performed a literature review and meta-analysis of 17 human trials considering the effect of MBL2 genotype and/or MBL levels and TB infection. No significant association was demonstrated between MBL2 genotype and pulmonary TB infection. However, the majority of studies did not report MBL2 haplotype inclusive of promoter polymorphisms. Serum MBL levels were shown to be consistently elevated in the setting of TB infection. While this may indicate that high MBL levels protect against infection with TB, the increase was also of a degree consistent with the acute-phase reaction. This analysis suggests that the relatively poorly characterized MBL2 genotypes reported are not associated significantly with susceptibility to pulmonary TB infection, but high MBL serum levels may be. Balanced polymorphisms

are the result of beneficial effects of resistance to prevalent infections due to physiological changes consequent on genetic variation. Well-characterized examples in human biology include haemoglobinopathies (sickle-cell and alpha-thalassaemia) and Plasmodium falciparum[1]. One of the most common polymorphisms on a global scale is that involving mannose-binding lectin (MBL), a pattern recognition receptor of the innate immune system. This liver-derived, acute-phase reactant recognizes pathogen-associated molecular patterns, CH5424802 in vitro PLEKHM2 killing microorganisms via activation of the lectin complement pathway and opsonophagocytosis [2,3]. MBL is also involved

in modulation of other inflammatory pathways contributing to autoimmune disease, apoptosis and vascular disease [4]. Despite its manifold effects in innate immune system pathways, there is a high frequency of MBL deficiency that arises due to polymorphisms of the MBL2 gene. The evolutionary advantage of MBL deficiency is unclear. MBL production is controlled by the MBL2 gene, and polymorphisms of the structural regions of the gene or its promoter are associated with relative or absolute serum MBL deficiencies [5]. The presence of key structural and promoter polymorphisms in a detailed MBL2 haplotype is reasonably well correlated with reduced serum MBL levels, and genotypic analyses are used frequently as surrogates for MBL serum levels. The MBL2 structural gene variants, B, C and D, are referred to collectively as O while A is the wild-type. Prior to recognition of the importance of MBL2 promoter polymorphism, MBL deficiency was defined on the basis of structural gene polymorphism alone and variably as the presence of any variant allele, [AO or OO] or compound heterozygosity for variant alleles [OO].

4 reside the peptides QIMYNYPAM (TB10.43–11) and IMYNYPAML (TB10.44–12). These peptides share the common motif ‘IMYNYPAM’ FK506 research buy and bound to six out of eight alleles (i.e. HLA-A*0201, A*0301, A*1101, A*2401, B*0702 and B*1501). At the C-terminus, we identified a different motif, MMARDTAE, shared by the peptides AMMARDTAE (TB10.482–90) and MMARDTAEA (TB10.483–91). This motif bound to three out of eight alleles (HLA-A*0201, B*0702 and B*1501; Table 1). We chose TB10.4 peptides and performed affinity (ED50) and off-rate (t1/2) analysis for (i) peptides identified as binders (above 20% compared with the positive control peptide), and (ii) MHC class I-binding epitopes below the 20% cut-off if they represented

the only peptides that bound to MHC class I alleles; for example, AMMARDTAE and MMARDTAEA for A*0101, and MMARDTAEA for B*0801. Affinity between candidate peptides and the respective MHC class I complex was found to be in the range of 60 nm to 800 μm, with the majority (75%) in the range of 1–80 μm. Different TB10.4 peptides bound with different affinity

to the same MHC allele; for example, the peptide QIMYNYPAM (TB10.43–11) bound with an affinity of 800 μm to the allele HLA-B*0702, while the peptide AMMARDTAE (TB10.482–90) bound with an affinity of 80 nm to the same MHC class I allele. Also, the identical peptide could bind with different affinity to different MHC class I alleles. For example, the peptide IMYNYPAML Akt inhibitor (TB10.44–12) bound to HLA-A*0201 with an affinity of 800 nm, to A*0301 with an affinity of 700 nm, to A*2402 with an

affinity of 100 nm, to B*0702 with an affinity of 30 μm and to B*1501 with an affinity of 20 μm. Overall, the TB10.4 peptides bound with higher affinity to HLA-A alleles than to HLA-B alleles (Fig. 3, Table 2). The off-rate assay was used to evaluate the relative stability of each MHC class I complex. The dissociation rate of the peptides spanned a wide range of < 1 to 27 hr, with the majority of epitopes (27 of 52) in the range of 1–3 hr. Four peptides, for example HLA-B*0702 RAYHAMSST (TB10.467–75), exhibited a dissociation rate of < 1 hr, while nine of 52 peptides showed a t1/2 value of more than 5 hr, for example HLA-A*0201 AMMARDTAE (TB10.482–90). We could identify differences both (i) within a single MHC class I allele presenting different Inositol oxygenase peptides, for example HLA-A*0201 which presents the peptide IMYNYPAML (TB10.44–12) with an off-rate of approximately 27 hr and GITYQAWQA (TB10.448–56) with an off-rate of 0·7 hr, and (ii) between different alleles presenting identical peptides, for example the peptide IMYNYPAML (TB10.44–12) which exhibited an off-rate of approximately 27 hr for HLA-A*0201, approximately 1 hr for A*0301, approximately 1·5 hr for A*2402/B*0702 and approximately 4 hr for B*1501. We could not find any correlation between affinity and off-rate; some peptides with high affinity had very long off-rates, while other peptides showed the opposite dissociation pattern (Fig. 3 and Table 2).

3M-003 produces a cytokine cascade in animals that resembles imiquimod (TLR-7 stimulation), but is a more potent activator of both TLR-7 and TLR-8 receptors than imiquimod (Gorden et al., 2006). The activation of macrophages by an imidazoquinoline resulting in significantly enhanced killing of C. albicans is a novel finding. Presumably, this is mediated via TLR engagement, the signaling pathways mentioned, and induction of the transcription factor NF-κB (Sauder, 2003). Most relevant to the induction of the antifungal activity in macrophages by this drug family are reports of imiquimod-induced macrophage killing of Leishmania donovani (Buates & Matlashewski,

1999, 2001). The authors showed that the killing activity Crizotinib datasheet of imiquimod-activated macrophages was due to upregulation of iNOS and NO production. This in vitro activity correlates with clinical antileishmanial activity (Arevalo et al., 2007). Imiquimod upregulation of iNOS and macrophage NO production is similar to IFN-γ activation of macrophages where iNOS is upregulated and

enhanced NO production is required for antifungal activity, for example against Histoplasma capsulatum (Brummer & Stevens, 1995). Because NO production contributes to the candidacidal activity of activated macrophages (Rementeria et al., 1995; Vazquez-Torres et al., 1996), we proposed that macrophages activated by 3M-003 exert candidacidal activity in a NO-dependent manner. Our data indicate that NO production plays a role in the candidacidal activity of 3M-003- or IFN-γ-activated macrophages. However, the role of NO in killing of C. albicans beta-catenin activation may be limited, and a full dose–response curve with MMA would be needed to specify the NO contribution. In contrast, NO production played a more substantial

selleck kinase inhibitor role in killing of H. capsulatum by IFN-γ+LPS-activated macrophages in our hands (Brummer & Stevens, 1995) or L. donovani by imiquimod- or IFN-γ+LPS-activated macrophages (Buates & Matlashewski, 1999). In contrast to the effect of 3M-003 on macrophages, 3M-003 did not significantly directly increase the candidacidal activity of monocytes or neutrophils. We speculate that, as with natural killer cells (Hart et al., 2005), a paucity of TLR-7 and TLR-8 on monocytes and neutrophils from mice might account for the poor responses to 3M-003 for the induction of candidacidal activity. Alternatively, these TLRs may respond differently in these cell types, and a different spectrum of responses, including different cytokines, may be produced. Only one of the three murine neutrophil subsets expresses TLR-7, and only one expresses TLR-8 (Tsuda et al., 2004). Mice do not have the benefit of a fully functional TLR-8 response to this drug family (Gorden et al., 2006). Imiquimod appears to stimulate macrophages through TLR-7 (Hemmi et al., 2002).

Despite being immortalized, HTR-8/SVneo cells have retained all the phenotypic and functional characteristics

of the parental Microbiology inhibitor mortal HTR-8 cells. The expressing markers of EVCT in situ are cytokeratins 18 and 8, human placental lactogen (hPL), human chorionic gonadotropin (hCG), human leukocyte antigen G (HLA-G) and type IV collagenase. Meanwhile, another immortalized primary cell clone (HPT-8) exhibited cytokeratin 7, cytokeratin 18, vimentin, cluster of differentiation antigen 9, epidermal growth factor receptor, stromal cell-derived factor 1 and placental alkaline phosphatase. They secreted prolactin, oestradiol, progesterone and hCG and were positive for HLA-G, a marker of extravillous trophoblasts.[14] These cells are permissive for the full replication cycle of human cytomegalovirus.[15, 16] These features make HTR-8/SVneo and HPT-8 cells as an ideal in vitro model for studying the biology of normal trophoblasts. Between October 2005 and January 2009, we recruited women who underwent induced abortion or experienced spontaneous abortion at Nanjing Maternity and Child Health Care Hospital. All of the women were asked about the number of previous CHIR-99021 manufacturer miscarriages, the number of stillbirths and the total number of previous pregnancies, and had placental villi and blood samples drawn. The same questionnaire was translated into the native

languages of the women and was used with participants from Nanjing Maternity and Child Health Care Hospital. The study included participants born in the same country who were all over 18 years of age. Women (n = 30) who had a previous history of spontaneous abortion, that is, (i) a history of two or more consecutive spontaneous abortions in the first trimester and (ii) an unexplained aetiology of spontaneous abortion with unexplained vaginal bleeding at 6-8 weeks of gestation, and for whom pregnancy

loss was confirmed by ultrasound scan were considered part of the spontaneous abortion group. Their average age was 28.8 years, and the average gestational age was 56.4 days. These subjects were age- and sex-matched Forskolin in vivo with 30 apparently healthy pregnant women who had no abnormal gynaecological history at 6–8 weeks of gestation and who wanted to have an induced abortion (control group). Their average age was 27.8 years, and the average gestational age was 56.6 days. These women voluntarily sought abortions for family planning purposes. Live pregnancy was confirmed by ultrasound scan. All of the women had regular menstrual cycles, and the gestational age estimates based on the last menstrual period was confirmed by the ultrasound scan. Termination of pregnancy was surgically achieved by vacuum suction as approved by the Ethical Committee of the Chinese Academy of Sciences and Nanjing Maternity and Child Health Care Hospital in Nanjing.

Toll-like receptors (TLRs) are type-I transmembrane proteins with extracellular leucine-rich repeat motifs and an intracellular Toll/interleukin-1 receptor domain, and they play important roles in recognition of microbial invasion.1 Numerous lines of evidence have indicated

that TLRs orchestrate not only the innate immune system but also adaptive immune responses to microbial infections.2 check details The TLR signals are known to induce activation of the nuclear factor-κB in antigen-presenting cells, which results in the expression of various cytokine genes, induction of co-stimulatory molecules, B7-1 (CD80) and B7-2 (CD86), and class II major histocompatibility complex molecules.3–5 Therefore, TLRs are able to orchestrate the adaptive immune responses to microbial infections. We have purified and characterized mycoplasmal diacylated lipoproteins responsible for see more the activation

of macrophages and fibroblasts6,7 and have synthesized a diacylated lipopeptide called FSL-1 [S-(2,3-bispalmitoyloxypropyl) CGDPKHPKSF] on the basis of the N-terminal structure of a 44 000 molecular weight Mycoplasma salivarium lipoprotein.7 We have also investigated various biological activities of FSL-18–11 and the mechanism by which it is recognized by TLRs.12–14 Recently, it was found that FSL-1 can enhance phagocytosis of bacteria by macrophages through a TLR2-mediated signalling pathway.10 In the course of these studies, we have become interested in how the TLR2 ligand FSL-1 is processed by macrophages after recognition. Although Triantafilou et al.15 recently reported that recognition of lipoteichoic acid (LTA), which had been considered Depsipeptide price to be a TLR2 ligand, occurs at the cell surface and that LTA is internalized in a lipid raft-dependent manner, details of internalization of TLR2 ligands after recognition

remain unknown. This study therefore was designed to investigate how the TLR2 ligand FSL-1 is processed in macrophages after recognition by TLR2. FSL-1 was synthesized as described previously,7 and fluorescein isothiocyanate-conjugated FSL-1 (FITC-FSL-1) was purchased from BioSynthesis (Lewisville, TX). Alexa Fluor 594-conjugated concanavalin A (Alexa-Con A), Lysotracker Red DND-99, and Alexa Fluor 594-conjugated anti-mouse immunoglobulin G were purchased from Invitrogen-Molecular Probes (Eugene, OR); nystatin (Nys), chlorpromazine (CPZ) and methyl-β-cyclodextrin (MbCD) were obtained from Sigma-Aldrich (St Louis, MO); anti-clathrin heavy chain monoclonal antibody (mAb) (clone X22) was obtained from Calbiochem-Novabiochem (La Jolla, CA); and anti-mouse/human TLR2 mAb (clone T2.5), and phycoerythrin-conjugated anti-mouse TLR2 mAb (clone 6C2) were obtained from eBioscience (San Diego, CA). Anti-human CD14 mAb (clone MY4) was obtained from Beckman Coulter (Fullerton, CA), and anti-human CD36 mAb (clone FA6-152) was obtained from Abcam (Cambridge, UK).

The self- /non-self-theory has pitfalls, and pregnancy is the main one for opponents. Antonio Countinho sees the immune system as: (a) networks, including anti-self natural autoantibodies12 and idiotype/anti-idiotype antibodies/T-cells. This has been relatively poorly studied in allopregnancy, despite reports13,14 that might be relevant to effects of intravenous immunoglobulins (IVIG) for recurrent spontaneous abortions (RSA). Matzinger’s ‘danger theory’15 stems from discussions on pregnancy with Robert Schwab (June 16, 1998 New York Times). For her, it implies that the immune system does not function by self /non-self, but instead reacts

to ‘danger’ signals such as inflammation, apoptosis, and bleeding. Thus, healthy foetuses are not rejected, simply because they do not send alarm signals. However, should Src inhibitor they become infected, the mother, in clearing infection, also rejects the foetus. ‘The danger model’ predicted an important role for antigen presenting cells (APCs) in turning tolerance on or off, and specific ‘danger receptors’, subsequently identified as Toll-like receptors. It offers an apparently elegant, though tautological, explanation

of allopregnancy INK128 as ‘it does not elicit danger’. Polly Matzinger states further: ‘reproduction cannot be a danger’…. ‘it does not make evolutionary sense’. This also explains why a conceptus still thrives in a pre-immunised host, as grafting produces micro wounds and local bleeding, while the foetus does not seem to do so. Danger was enunciated before the 1989–1991 papers describing implantation as requiring local inflammation and ignores that invasion is accompanied by apoptosis,16 local bleeding and in equids there are zones of quasi rejections in the placenta with a massive maternal lymphocytic infiltrate.17 Rebamipide It is also difficult to explain by the danger model why, in murine abortion,18 some foetuses are rejected, whereas in the same mother, others are not, both being not infected.

However, CBA × DBA/2 embryos can be rescued by pre-culture in CSF-conditioned medium before transfer to a CBA foster mother, suggesting that these embryos are not fully ‘normal’.19 Danger might explain why the CBA × DBA/2 system is environmentally dependent,20 although surprisingly, the LPS content of faeces does not correlate with abortion.21 Danger, however, does not explain why CBA × DBA/2 and DBA/2 × CBA matings are seen differentially (gene imprinting experiments of A. Paldi) and why immunisation against paternal MHC antigens corrects ‘danger’,22 even how immunisation permits pregnancy in case of donkey embryos implanted in mare (the donkey in horse pregnancy).15 Finally, Matzinger did not envisage alloantigen-specific mechanisms regulating only the anti-foetal reactions. Moreover, what she describes is exactly opposite to some cases of infections, such as local, e.g. uterine Listeria.