Investigation of Mandarin Word Production in Children and Adults: Evidence from Phonological Priming with Non-words.

Using a cross-modal picture-word interference (PWI) task, we examined phonological representations and encoding in Mandarin-speaking children and adults. Pictures of monosyllabic words were presented visually, with auditory primes presented before, concurrent with, or after the picture's appearance (SOA -200, -100, 0, +150). Primes were related to the targets in terms of Onset, Rhyme, Tone, Onset and Tone, Rhyme and Tone, or were unrelated. The rhymes of target words were counterbalanced between simple and complex structures to examine effects of rhyme complexity. Twenty Mandarin-speaking adults (aged 20;3 to 23;10), 20 school-age children (aged 9;1 to 10;11) and 20 preschoolers (aged 5;0 to 5;11) were asked to name the pictures as quickly as possible while ignoring the primes played over a headset. The results showed that adults exhibited consistent Onset and Onset-Tone priming effects across later SOAs, while the older children (9- to 10-year-olds) exhibited Onset, Rhyme, Onset-Tone and Rhyme-Tone priming effects across later SOAs. The younger children (5-year-olds), in contrast, exhibited Rhyme and Rhyme-Tone priming effects at the earliest SOA. For both groups of children, Rhyme and Rhyme-Tone priming effects were complexity-dependent. Our findings suggest that the phonological representations of Mandarin speakers develop from holistic units into those with an onset-based structure. Moreover, an incremental processing pattern at the sub-syllabic level is gradually developed around the age of 9 or 10, though susceptibility to holistic phonological similarity is retained to some degree.

Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralising antibodies in vaccinated solid-organ transplant recipients.

Objectives: The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). A 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, yet their immune responses are less effective compared to healthy controls (HCs). Methods: We analyzed the humoral immune responses against the vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant in 113 SOTRs, of whom 44 had recovered from COVID-19 (recovered-SOTRs) and 69 had not contracted the virus (COVID-naïve). In addition, 30 HCs, 8 of whom had recovered from COVID-19, were also studied. Results: Here, we report that three doses of the mRNA vaccine had only a modest effect in eliciting anti-viral antibodies against all viral strains in the fully vaccinated COVID-naive SOTRs (n = 47). Only 34.0% of this group of patients demonstrated both detectable anti-RBD IgG with neutralization activities against alpha, beta, and delta variants, and only 8.5% of them showed additional omicron neutralizing capacities. In contrast, 79.5% of the recovered-SOTRs who received two doses of vaccine demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. Conclusion: These findings illustrate a significant impact of previous infection on the development of anti-SARS-CoV-2 immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population.

Adlay Testa (Coix lachryma-jobi L. var. Ma-yuen Stapf.) Ethanolic Extract and Its Active Components Exert Anti-Proliferative Effects on Endometrial Cancer Cells via Cell Cycle Arrest.

Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been demonstrated to have bioactive polyphenols, flavonoids, phytosterols, and essential nutrients for health benefits, including anticancer effects in humans. However, little is known about the effect of adlay seeds on endometrial cancer. Our study aimed to investigate the potential growth inhibitory effects of several adlay seed fractions, including ethyl acetate (ATE-EA) and its bioactive constituents, separately on endometrial cancer cells-HEC-1A (phosphatase and tensin homolog-positive) and RL95-2 (phosphatase and tensin homolog-negative)-and identify related active ingredients. In addition, the potential active fractions and the phytochemical compounds were elucidated. The results demonstrate superior activity of ATE-EA with significant in vitro cell proliferation inhibitory capacity, particularly its C.D.E.F-subfraction. Moreover, HPLC- and GC/FID-based quantification of ATE-EA subfractions showed that phenolic compounds (caffeic acid, protocatechuic acid, and p-hydroxybenzaldehyde), flavonoids, steroids, and fatty acid compounds exert anti-proliferative effects in the cell model. Finally, it was shown that cell growth and cell cycle arrest most significantly occurred in the in G1 or G2/M phase under ATE-EA treatment. Collectively, our results demonstrate an antiproliferative effect of ATE-EA on endometrial cancer cells that suggest a positive health outcome for women from consumption of these compounds.

Genetic Risk Stratification: A Paradigm Shift in Prevention of Coronary Artery Disease.

Coronary artery disease (CAD) is a pandemic disease that is highly preventable as shown by secondary prevention. Primary prevention is preferred knowing that 50% of the population can expect a cardiac event in their lifetime. Risk stratification for primary prevention using the American Heart Association/American College of Cardiology predicted 10-year risk based on conventional risk factors for CAD is less than optimal. Conventional risk factors such as hypertension, cholesterol, and age are age-dependent and not present until the sixth or seventh decade of life. The genetic risk score (GRS), which is estimated from the recently discovered genetic variants predisposed to CAD, offers a potential solution to this dilemma. The GRS, which is derived from genotyping the population with a microarray containing these genetic risk variants, has indicated that genetic risk stratification based on the GRS is superior to that of conventional risk factors in detecting those at high risk and who would benefit most from statin therapy. Studies performed in >1 million individuals confirmed genetic risk stratification is superior and primarily independent of conventional risk factors. Prospective clinical trials based on risk stratification for CAD using the GRS have shown lifestyle changes, physical activity, and statin therapy are associated with 40% to 50% reduction in cardiac events in the high genetic risk group (20%). Genetic risk stratification has the advantage of being innate to an individual's DNA, and because DNA does not change in a lifetime, it is independent of age. Genetic risk stratification is inexpensive and can be performed worldwide, providing risk analysis at any age and thus has the potential to revolutionize primary prevention.

A Journey through Genetic Architecture and Predisposition of Coronary Artery Disease.

INTRODUCTION: To halt the spread of coronary artery disease (CAD), the number one killer in the world, requires primary prevention. Fifty percent of all Americans are expected to experience a cardiac event; the challenge is identifying those at risk. 40 to 60% of predisposition to CAD is genetic. The first genetic risk variant, 9p21, was discovered in 2007. Genome-Wide Association Studies has since discovered hundreds of genetic risk variants. The genetic burden for CAD can be expressed as a single number, Genetic Risk Score (GRS). Assessment of GRS to risk stratify for CAD was superior to conventional risk factors in several large clinical trials assessing statin therapy, and more recently in a population of nearly 500,000 (UK Biobank). Studies were performed based on prospective genetic risk stratification for CAD. These studies showed that a favorable lifestyle was associated with a 46% reduction in cardiac events and programmed exercise, a 50% reduction in cardiac events. Genetic risk score is superior to conventional risk factors, and is markedly attenuated by lifestyle changes and drug therapy. Genetic risk can be determined at birth or any time thereafter. CONCLUSION: Utilizing the GRS to risk stratify young, asymptomatic individuals could provide a paradigm shift in the primary prevention of CAD and significantly halt its spread.

Dietary Glycotoxins, Advanced Glycation End Products, Inhibit Cell Proliferation and Progesterone Secretion in Ovarian Granulosa Cells and Mimic PCOS-like Symptoms.

Women with polycystic ovary syndrome (PCOS) have been reported to have an elevated serum advanced glycation end product (AGE) level. However, the effect of AGEs on the pathophysiological ovarian granulosa cells of PCOS is still unclear. In this study, five indented BSA-derived AGE products were used to evaluate their effect on the function of human granulosa cells. We found that the proliferation of both primary human ovarian granulosa (hGC) cells and human granulosa-like tumor (KGN) cells were inhibited by treatment with these five AGE products. The progesterone secretion level was also reduced in both hGC and KGN cells by treatment with these AGE products through downregulation of LH receptor/cAMP regulatory activity. The granulosa cell layer and serum progesterone level were reduced in rats by treatment with MG-BSA; moreover, an increased number of follicle cysts and an irregular estrous cycle were observed. MG-BSA treatment had a similar effect on the phenotypes of the DHEA-induced PCOS model. Additionally, the insulin resistance and hepatic lesions seen in the DHEA-induced PCOS model were observed in the MG-BSA treatment group. Taken together, we found that AGEs exert a toxic effect on ovarian granulosa cells, ovarian morphology, and the estrous cycle that mimics the DHEA-induced PCOS phenotypes.

New Dammarane-type Saponins from Gynostemma pentaphyllum.

Six new dammarane-type saponins, gypenosides CP1-6 (16), along with 19 known compounds 7⁻25, were isolated and characterized from the aerial parts of Gynostemma pentaphyllum. Among these compounds, eight dammarane-type saponins, 2, 5, 6, 7, 11, 12, 13, and 15, exhibited the greatest antiproliferative effects against two human tumor cell lines (A549 and HepG2).

Protective Effect of Melatonin against Oxidative Stress-Induced Apoptosis and Enhanced Autophagy in Human Retinal Pigment Epithelium Cells.

Age-related macular degeneration (AMD) affects the retinal macula and results in loss of vision, and AMD is the primary cause of blindness and severe visual impairment among elderly people worldwide. AMD is characterized by the accumulation of drusen in the Bruch's membrane and dysfunction of retinal pigment epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD remains unclear, and no effective treatment exists. Accumulating evidence indicates that oxidative stress plays a critical role in RPE cell degeneration and AMD. Melatonin is an antioxidant that scavenges free radicals, and it has anti-inflammatory, antitumor, and antiangiogenic effects. This study investigated the antioxidative, antiapoptotic, and autophagic effects of melatonin on oxidative damage to RPE cells. We used hydrogen peroxide (H2O2) to stimulate reactive oxygen species production to cause cell apoptosis in ARPE-19 cell lines. Our findings revealed that treatment with melatonin significantly inhibited H2O2-induced RPE cell damage, decreased the apoptotic rate, increased the mitochondrial membrane potential, and increased the autophagy effect. Furthermore, melatonin reduced the Bax/Bcl-2 ratio and the expression levels of the apoptosis-associated proteins cytochrome c and caspase 7. Additionally, melatonin upregulated the expression of the autophagy-related proteins LC3-II and Beclin-1 and downregulated the expression of p62. Thus, melatonin's effects on autophagy and apoptosis can protect against H2O2-induced oxidative damage in human RPE cells. Melatonin may have multiple protective effects on human RPE cells against H2O2-induced oxidative damage.

Hexane fraction of adlay (Coix lachryma-jobi L.) testa ethanolic extract inhibits human uterine sarcoma cancer cells growth and chemosensitizes human uterine sarcoma cells to doxorubicin.

BACKGROUND: Cancer has remained among the top ten causes of death in Taiwan since 1982. Uterine sarcoma is a rare gynecologic cancer, and chemotherapy is one type of cancer treatment. Doxorubicin (Dox) is widely used for treating several cancers, including uterine sarcoma, however, multidrug resistance (MDR) is a major clinical problem and a critical cause of treatment failure. The ethanolic extracts of adlay testa (ATE) exhibited significant anticancer activities against many cancer types. PURPOSE: In this study we investigated the antitumor effects of the hexane fraction of the adlay testa ethanolic extracts (ATE-Hex) on the human uterine sarcoma cancer cell line MES-SA, as well as on the multidrug-resistant human uterine sarcoma cancer cell line MES-SA/Dx5. METHODS: The MTT assay was performed to assess the effects of the extracts of different parts of the adlay on the proliferation of human uterine sarcoma cells (MES-SA and MES-SA/Dx5) and human uterine smooth muscle cells (HUtSMCs). To determine whether ATE-Hex has a chemosensitizing effect on drug-resistant uterine sarcoma cells, the MTT assay was performed to examine the synergistic effects of ATE-Hex, the chemotherapeutic drug Dox alone, and in combination. Rhodamine accumulation was analyzed using fluorescence detection. Apoptotic cells were analyzed via flow cytometry. In addition, employing a flame ionization detector (GC/FID) gas chromatography was also developed as the analysis platform for ATE-Hex. RESULTS: The results demonstrated that ATE-Hex exhibited the best effects of inhibition on MES-SA and MES-SA/Dx5 cells. Co-treatment of ATE-Hex and Dox could synergistically inhibit the proliferation of cancer cells. ATE-Hex reduced the rhodamine efflux in MES-SA/Dx5 cells, indicating that ATE-Hex could reduce the expression of P-gp. In addition, our results showed that treatment with ATE-Hex alone or in combination with Dox significantly inhibited the growth of cancer cells and induced apoptosis by increasing the sub-G1 phase and poly(ADP-ribose) polymerase (PARP) being cleaved. Flow cytometry revealed that ATE-Hex induced apoptosis. CONCLUSION: These results suggest that ATE-Hex can inhibit human uterine sarcoma cancer cells by inducing apoptosis and increasing the chemosensitivity of the multidrug-resistant human uterine sarcoma cancer cell MES-SA/Dx5 to Dox. Furthermore, the combination of ATE-Hex and Dox could decrease MDR and increase the synergistic effect.

ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth.

The blockade of immune checkpoints by anti-receptor and/or anti-ligand mAb is one of the most promising approaches to cancer immunotherapy. The interaction between Ig-like transcript 3 (ILT3), a marker of tolerogenic dendritic cells, also known as LILRB4/LIR5/CD85k, and its still unidentified ligand on the surface of activated human T cells is potentially important for immune checkpoint blockade. To identify the ILT3 ligand, we generated mAb by immunizing mice with Jurkat acute T cell leukemia, which binds ILT3.Fc to its membrane. Flow cytometry, mass spectrometry, and Biacore studies demonstrated that the ILT3 ligand is a CD166/activated leukocyte cell adhesion molecule. Knockdown of CD166 in primary human T cells by nucleofection abolished the capacity of ILT3.Fc to inhibit CD4+ Th cell proliferation and to induce the generation of CD8+CD28- T suppressor cells. CD166 displays strong heterophilic interaction with CD6 and weaker homophilic CD166-CD166 cell adhesion interaction. ILT3.Fc inhibited the growth of CD166+ tumor cell lines (TCL) derived from lymphoid malignancies in vitro and in vivo. CRISPR-Cas9-based knockout of CD166 from TCL abrogated ILT3.Fc binding and its tumor-inhibitory effect. The mechanism underlying the effect of ILT3.Fc on tumor cell growth involves inhibition of the p70S6K signaling pathway. Blockade of CD166 by ILT3.Fc inhibited progression of human TCL in NOD.Cg-Prkdc Il-2rg/SzJ mice, suggesting its potential immunotherapeutic value.

Molecular and Cellular Characterization of Human CD8 T Suppressor Cells.

Bidirectional interactions between dendritic cells and Ag-experienced T cells initiate either a tolerogenic or immunogenic pathway. The outcome of these interactions is of crucial importance in malignancy, transplantation, and autoimmune diseases. Blockade of costimulation results in the induction of T helper cell anergy and subsequent differentiation of antigen-specific CD8+ T suppressor/regulatory cells (Ts). Ts, primed in the presence of inhibitory signals, exert their inhibitory function in an antigen-specific manner, a feature with tremendous clinical potential. In transplantation or autoimmunity, antigen-specific Ts can enforce tolerance to auto- or allo-antigens, while otherwise leaving the immune response to pathogens uninhibited. Alternatively, blockade of inhibitory receptors results in the generation of cytolytic CD8+ T cells, which is vital toward defense against tumors and viral diseases. Because CD8+ T cells are MHC Class I restricted, they are able to recognize HLA-bound antigenic peptides presented not only by APC but also on parenchymal cells, thus eliciting or suppressing auto- or allo-immune reactions.

Preparation and characterization of a novel Al(18)F-NOTA-BZA conjugate for melanin-targeted imaging of malignant melanoma.

Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel (18)F-labeled NOTA-benzamide conjugate, Al(18)F-NOTA-BZA, which can be synthesized in 30min with a radiochemical yield of 20-35% and a radiochemical purity of >95%. Al(18)F-NOTA-BZA is highly hydrophilic (logP=-1.96) and shows good in vitro stability. Intravenous administration of Al(18)F-NOTA-BZA in two melanoma-bearing mouse models revealed highly specific uptake in B16F0 melanotic melanoma (6.67±0.91 and 1.50±0.26%ID/g at 15 and 120min p.i., respectively), but not in A375 amelanotic melanoma (0.87±0.21 and 0.24±0.09%ID/g at 15 and 120min p.i., respectively). The clearance from most normal tissues was fast. A microPET scan of Al(18)F-NOTA-BZA-injected mice also displayed high-contrast tumor images as compared with normal organs. Owing to the favorable in vivo distribution of Al(18)F-NOTA-BZA after intravenous administration, the estimated absorption dose was low in all normal organs and tissues. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and thelow projected human dosimetry supported that Al(18)F-NOTA-BZA is a very promising melanin-specific PET probe for melanin-positive melanoma.

Synthesis and characterization of a novel radioiodinated phenylacetamide and its homolog as theranostic agents for malignant melanoma.

Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. This study reports the preparation and biological characterizations of N-(2-(diethylamino)ethyl)-2-(3-(123/131)I-iodo-4- hydroxyphenyl)acetamide and N-(2-(diethylamino)ethyl)-3-(3-(123/131)I-iodo-4-hydroxyphenyl)propanamide (123/131)I-IHPA and 123/131I-IHPP) as novel melanin-specific theranostic agents. These two tracers were hydrophilic, exhibited good serum stability and high binding affinity to melanin. In vitro and in vivo studies revealed rapid, high and tenacious uptakes of both 131I-IHPA and 131I-IHPP in melanotic B16F0 cell line and in C57BL/6 mice bearing B16F0 melanoma, but not in amelanonic A375 cell line and tumors. Small-animal SPECT imaging also clearly delineate B16F0 melanoma since 1 h postinjection of 123I-IHPA and 123I-IHPP in tumor-bearing mice. Owing to the favorable biodistribution of 131I-IHPA and 131I-IHPP after intravenous administration, the estimated absorption dose was low in most normal organs and relatively high in melanotic tumor. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and acceptable projected human dosimetry supported that these two tracers are promising theranostic agents for melanin-positive melanoma.

Synthesis and evaluation of ¹²³/¹³¹I-Iochlonicotinamide as a novel SPECT probe for malignant melanoma.

Malignant melanoma expresses a highly aggressive metastasis. Early diagnosis of malignant melanoma is important for patient survival. Radiolabeled benzamides and nicotinamides have been reported to be attractive candidates for malignant melanoma diagnosis as they bind to melanin, a characteristic substance that displays in malignant melanoma, and show high tumor accumulation and retention. Herein, we designed and synthesized a novel (123/131)I-labeled nicotinamide derivative that specifically binds to melanin. (123/131)I-Iochlonicotinamide was prepared with good radiochemical yield (50-70%, decay corrected) and high specific radioactivity (50-80 GBq/µmol). (131)I-Iochlonicotinamide exhibited good in vitro stability (radiochemical purity >95% after a 24-h incubation) in human serum. High uptake of (123/131)I-Iochlonicotinamide in B16F0 melanoma cells compared to that in A375 amelanotic cells demonstrated its selective binding to melanin. Intravenous administration of (123/131)I-Iochlonicotinamide in a melanoma-bearing mouse model revealed high uptake in melanotic melanoma and high tumor-to-muscle ratio. MicroSPECT scan of (123/131)I-Iochlonicotinamide injected mice also displayed high contrast tumor imaging as compared with normal organs. The radiation-absorbed dose projection for the administration of (131)I-Iochlonicotinamide to human was based on the results of biodistribution study. The effective dose appears to be approximately 0.44 mSv/MBq(-1). The specific binding of (123/131)I-Iochlonicotinamide to melanin along with a prolonged tumor retention and acceptable projected human dosimetry suggest that it may be a promising theranostic agent for treating malignant melanoma.

ILT3.Fc inhibits the production of exosomes containing inflammatory microRNA in supernatants of alloactivated T cells.

Immune activation needs to be tightly regulated to control immune-mediated tissue damage. Inhibitory pathways serve to terminate an immune response and resolve inflammation. Persistent exposure to antigens can drive development of adaptive regulatory cells. Similarly exposure of activated T cells to the recombinant ILT3-Fc molecule during priming triggers the differentiation of CD8 T suppressor cells and the induction of CD4 T helper anergy. Ts express high levels of immunoregulatory signature genes together with low levels of microRNA which control their function. Analysis of microRNA contained by exosomes from cultures in which T cells were alloactivated in the presence or absence of ILT3.Fc, demonstrated that this agent inhibits the release of inflammatory microRNA. The source of such inflammatory microRNA was found to reside in alloactivated CD4 T cells, since exosomes from MLC primed CD4 T cells were shown to diminish the suppressive activity of ILT3-Fc-induced CD8(+) Ts at high effector to suppressor T cell ratios. This indicates that inflammatory exosomes can swing the balance between effector and regulatory T cells in favor of immunity. These data suggest that isolation and characterization of micro-RNA containing exosomes in patients' circulation may be of use for treatment, prevention and monitoring of immune activation.

Downregulation of inflammatory microRNAs by Ig-like transcript 3 is essential for the differentiation of human CD8(+) T suppressor cells.

We have investigated the mechanism underlying the immunoregulatory function of membrane Ig-like transcript 3 (ILT3) and soluble ILT3Fc. microRNA (miRNA) expression profile identified genes that were downregulated in ILT3-induced human CD8(+) T suppressor cells (Ts) while upregulated in T cells primed in the absence of ILT3. We found that miR-21, miR-30b, and miR-155 target the 3'-untranslated region of genes whose expression was strongly increased in ILT3Fc-induced Ts, such as dual specificity phosphatase 10, B cell CLL/lymphoma 6, and suppressor of cytokine signaling 1, respectively. Transfection of miRNA mimics or inhibitors and site-specific mutagenesis of their 3'-untranslated region binding sites indicated that B cell CLL/lymphoma 6, dual specificity phosphatase 10, and suppressor of cytokine signaling 1 are direct targets of miR-30b, miR-21, and miR-155. Primed CD8(+) T cells transfected with miR-21&30b, miR-21&155, or miR-21&30b&155 inhibitors displayed suppressor activity when added to autologous CD3-triggered CD4 T cells. Luciferase reporter assays of miR-21 and miR-155 indicated that their transcription is highly dependent on AP-1. Analysis of activated T cells showed that ILT3Fc inhibited the translocation to the nucleus of the AP-1 subunits, FOSB and c-FOS, and the phosphorylation of ZAP70 and phospholipase C-γ 1. In conclusion, ILT3Fc inhibits T cell activation and induces the generation of Ts targeting multiple inflammatory miRNA pathways.

Gene profile analysis of CD8(+) ILT3-Fc induced T suppressor cells.

Gene profile analysis of ILT3-Fc-induced Ts revealed a significant upregulation of Zink finger proteins, most of which act as transcriptional repressors. Included among these repressors is BCL6, which was shown to play a critical role in the differentiation of ILT3-Fc-induced T suppressor (Ts) cells. Genes implicated in cell cycle progression were downregulated. Genes encoding numerous inflammatory cytokines and chemokines were also downregulated. In contrast, antiapoptotic genes, as well as members of the WNT and transforming growth factor-ß pathways, were upregulated. This study elucidates certain important aspects of Ts differentiation and function.

BCL6 is required for differentiation of Ig-like transcript 3-Fc-induced CD8+ T suppressor cells.

Ig-like transcript 3 (ILT3) is an inhibitory receptor expressed by tolerogenic dendritic cells. When human CD8(+) T cells are allostimulated in the presence of recombinant ILT3-Fc protein, they differentiate into antigenic specific T suppressor (Ts) cells that inhibit CD4 and CD8 T cell effector function both in vitro and in vivo. ILT3-Fc-induced CD8(+) Ts cells express high amounts of BCL6 that are crucial to their function. Knockdown of BCL6 from unprimed human T cells prevents their differentiation into Ts cells, whereas ex vivo overexpression of BCL6 converts CD8(+) T cells into Ts cells. NOD/SCID mice transplanted with human pancreatic islets and humanized by injection of human PBMCs tolerate the graft and develop BCL6(high) CD8(+) Ts cells when treated with ILT3-Fc before or after the onset of rejection. This indicates that ILT3-Fc acts through BCL6 and is a potent immunosuppressive agent for reversing the onset of allo- or possibly autoimmune attacks against pancreatic islets.

Membrane and soluble ILT3 are critical to the generation of T suppressor cells and induction of immunological tolerance.

The tolerogenic phenotype of human dendritic cells is characterized by high cell surface expression of the inhibitory receptor ILT3. ILT3 signals both intracellularly inhibiting tyrosine phosphorylation, NF-kappaB and MAPK p38 activity, transcription of certain co-stimulatory molecules, secretion of cytokines and chemokines, and extracellularly into the T cells with which the dendritic cells interact. Both ILT3(high) tolerogenic dendritic cells and soluble ILT3 induce CD4 Th anergy and differentiation of antigen specific CD8 T suppressor cells. Recombinant ILT3-Fc protein has important immunotherapeutic potential acting directly on activated T cells and promoting the induction of immunological tolerance.