Application of the Banff Human Organ Transplant Panel to kidney transplant biopsies with features suspicious for antibody-mediated rejection.

The Banff Classification for Allograft Pathology includes the use of gene expression in the diagnosis of antibody-mediated rejection (AMR) of kidney transplants, but a predictive set of genes for classifying biopsies with 'incomplete' phenotypes has not yet been studied. Here, we developed and assessed a gene score that, when applied to biopsies with features of AMR, would identify cases with a higher risk of allograft loss. To do this, RNA was extracted from a continuous retrospective cohort of 349 biopsies randomized 2:1 to include 220 biopsies in a discovery cohort and 129 biopsies in a validation cohort. The biopsies were divided into three groups: 31 that fulfilled the 2019 Banff Criteria for active AMR, 50 with histological features of AMR but not meeting the full criteria (Suspicious-AMR), and 269 with no features of active AMR (No-AMR). Gene expression analysis using the 770 gene Banff Human Organ Transplant NanoString panel was carried out with LASSO Regression performed to identify a parsimonious set of genes predictive of AMR. We identified a nine gene score that was highly predictive of active AMR (accuracy 0.92 in the validation cohort) and was strongly correlated with histological features of AMR. In biopsies suspicious for AMR, our gene score was strongly associated with risk of allograft loss and independently associated with allograft loss in multivariable analysis. Thus, we show that a gene expression signature in kidney allograft biopsy samples can help classify biopsies with incomplete AMR phenotypes into groups that correlate strongly with histological features and outcomes.

A Simple Molecular Tool for the Assessment of Kidney Transplant Biopsies.

BACKGROUND: The Banff Classification for Allograft Pathology recommendations for the diagnosis of kidney transplant rejection includes molecular assessment of the transplant biopsy. However, implementation of molecular tools in clinical practice is still limited, partly due to the required expertise and financial investment. The reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) assay is a simple, rapid, and inexpensive assay that permits simultaneous evaluation of a restricted gene panel using paraffin-embedded tissue blocks. The aim of this study was to develop and validate a RT-MLPA assay for diagnosis and classification of rejection. METHODS: A retrospective cohort of 220 kidney transplant biopsies from two centers, which included 52 antibody-mediated rejection, 51 T-cell-mediated rejection, and 117 no-rejection controls, was assessed. A 17-gene panel was identified on the basis of relevant pathophysiological pathways. A support vector machine classifier was developed. A subset of 109 biopsies was also assessed using the Nanostring Banff Human Organ Transplant panel to compare the two assays. RESULTS: The support vector machine classifier train and test accuracy scores were 0.84 and 0.83, respectively. In the test cohort, the F1 score for antibody-mediated rejection, T-cell-mediated rejection, and control were 0.88, 0.86, and 0.69, respectively. Using receiver-operating characteristic curves, the area under the curve for class predictions was 0.96, 0.89, and 0.91, respectively, with a weighted average at 0.94. Classifiers' performances were highest for antibody-mediated rejection diagnosis with 94% correct predictions, compared with 88% correct predictions for control biopsies and 60% for T-cell-mediated rejection biopsies. Gene expression levels assessed by RT-MLPA and Nanostring were correlated: r = 0.68, P < 0.001. Equivalent gene expression profiles were obtained with both assays in 81% of the samples. CONCLUSIONS: The 17-gene panel RT-MLPA assay, developed here for formalin-fixed paraffin-embedded kidney transplant biopsies, classified kidney transplant rejection with an overall accurate prediction ratio of 0.83. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_04_10_CJN10100822.mp3.

Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.

Diagnostic application of transcripts associated with antibody-mediated rejection in kidney transplant biopsies.

BACKGROUND: The diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of 'increased expression of thoroughly validated gene transcripts/classifiers strongly associated with AMR' as diagnostic criteria. METHOD: We used quantitative real-time polymerase chain reaction for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27), biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts [suspicious for AMR (AMRsusp), n = 49] and biopsies that would never meet criteria for AMR (No-AMR, n = 221). RESULTS: A 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score among the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low; n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio (HR) for graft loss (GL) in the AMRsusp group (HR = 1.109, P = 0.004 and HR = 1.138, P = 0.012, respectively), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination, respectively, for GL when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort. CONCLUSIONS: This study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of GL in biopsies that are suspicious for AMR but do not meet full criteria.

Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death.

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte-endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets.

COVID-19 varies from a mild illness in some people to fatal disease in others. Patients with severe disease tend to be older and have underlying medical problems. People with kidney failure have a particularly high risk of developing severe or fatal COVID-19. Patients with severe COVID-19 have high levels of inflammation, causing damage to tissues around the body. Many drugs that target inflammation have already been developed for other diseases. Therefore, to repurpose existing drugs or design new treatments, it is important to determine which proteins drive inflammation in COVID-19. Here, Gisby, Clarke, Medjeral-Thomas et al. measured 436 proteins in the blood of patients with kidney failure and compared the levels between patients who had COVID-19 to those who did not. This revealed that patients with COVID-19 had increased levels of hundreds of proteins involved in inflammation and tissue injury. Using a combination of statistical and machine learning analyses, Gisby et al. probed the data for proteins that might predict a more severe disease progression. In total, over 200 proteins were linked to disease severity, and 69 with increased risk of death. Tracking how levels of blood proteins changed over time revealed further differences between mild and severe disease. Comparing this data with a similar study of COVID-19 in people without kidney failure showed many similarities. This suggests that the findings may apply to COVID-19 patients more generally. Identifying the proteins that are a cause of severe COVID-19 ­ rather than just correlated with it ­ is an important next step that could help to select new drugs for severe COVID-19.

Molecular assessment of antibody-mediated rejection in human pancreas allograft biopsies.

Pancreas transplant longevity is limited by immune rejection, which is diagnosed by graft biopsy using the Banff Classification. The histological criteria for antibody-mediated rejection (AMR) are poorly reproducible and inconsistently associated with outcome. We hypothesized that a 34-gene set associated with antibody-mediated rejection in other solid organ transplants could improve diagnosis in pancreas grafts. The AMR 34-gene set, comprising endothelial, natural killer cell and inflammatory genes, was quantified using the NanoString platform in 52 formalin-fixed, paraffin-embedded pancreas transplant biopsies from 41 patients: 15 with pure AMR or mixed rejection, 22 with T cell-mediated rejection/borderline and 15 without rejection. The AMR 34-gene set was significantly increased in pure AMR and mixed rejection (P = .001) vs no rejection. The gene set predicted histological AMR with an area under the receiver operating characteristic curve (ROC AUC) of 0.714 (P = .004). The AMR 34-gene set was the only biopsy feature significantly predictive of allograft failure in univariate analysis (P = .048). Adding gene expression to DSA and histology increased ROC AUC for the prediction of failure from 0.736 to 0.770, but this difference did not meet statistical significance. In conclusion, assessment of transcripts has the potential to improve diagnosis and outcome prediction in pancreas graft biopsies.

Disease severity in patients with visceral leishmaniasis is not altered by co-infection with intestinal parasites.

Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity.

Mycobacterium tuberculosis-specific CD4+ T-cell response is increased, and Treg cells decreased, in anthelmintic-treated patients with latent TB.

In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection (Strongyloides or Schistosoma), and tested T-cell responses before and after anthelmintic treatment. The study was performed in migrants resident in the United Kingdom, where reexposure and reinfection following anthelmintic treatment would not occur. The frequency of CD4(+) IFN-γ(+) T cells was measured following stimulation with Mtb Purified Protein Derivative or ESAT-6/CFP-10 antigen, and concentrations of IFN-γ in culture supernatants measured by ELISA and multiplex bead array. Helminth infection was associated with a lower frequency of CD4(+) IFN-γ(+) T cells, which increased following treatment. Patients with helminth infection showed a significant increase in CD4(+) FoxP3(+) T cells (Treg) compared to those without helminth infection. There was a decrease in the frequency of Treg cells, and an associated increase in CD4(+) IFN-γ(+) T cells after the anthelmintic treatment. Here, we show a potential role of Treg cells in reducing the frequency and function of antimycobacterial CD4(+) IFN-γ(+) T cells, and that these effects are reversed after anthelmintic treatment.

Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study.

BACKGROUND: With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis. METHODS: Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months' follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months. RESULTS: Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95% confidence interval (CI), p-value) -1488.6 pg/ml ((-2682.5, -294.8), p = 0.01), and IL- 2 (-213.1 pg/ml (-419.2, -7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95% CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6. CONCLUSIONS: IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries. TRIAL REGISTRATION: ISRCTN registry, ISRCTN15705625. Registered on 30(th) September 2015.

Impact of co-infections and BCG immunisation on immune responses among household contacts of tuberculosis patients in a Ugandan cohort.

BACKGROUND: Tuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic. METHODS: Adults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models. RESULTS: We enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39-2.66; 0.96); hookworm, 2.81 (0.56-14.14; 0.20); malaria, 1.06 (0.48-2.35; 0.87); HIV, 0.74 (0.22-2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09-0.42), <0.0001; IL-2 0.34 (0.20-0.59), <0.0001; and TNFα 0.36 (0.16-0.79), 0.01. CONCLUSIONS: We found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.

Adult T cell leukemia/lymphoma: FoxP3(+) cells and the cell-mediated immune response to HTLV-1.

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma (ATLL) in ∼5% of HTLV-1-infected people. ATLL cells frequently express several molecules that are characteristic of regulatory T cells (Tregs), notably CD4, CD25 and the transcription factor FoxP3. It has therefore recently been suggested that HTLV-1 selectively infects and transforms Tregs. We show that HTLV-1 induces and maintains a high frequency of FoxP3+ T cells by inducing expression of the chemokine CCL22; the frequency is especially high in patients with chronic ATLL. In turn, the FoxP3+ T cells exert both potentially beneficial and harmful effects: they suppress the growth of autologous ATLL clones and may also suppress the host's cytotoxic T lymphocyte response, which normally limits HTLV-1 replication and reduces the risk of HTLV-1-associated diseases. Although ATLL cells may exert immune suppressive effects, we conclude that ATLL is not necessarily a tumour of classical FoxP3+ Tregs.

Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs.

Human T-cell leukemia virus type 1 (HTLV-1) codes for 9 alternatively spliced transcripts and 2 major regulatory proteins named Tax and Rex that function at the transcriptional and posttranscriptional levels, respectively. We investigated the temporal sequence of HTLV-1 gene expression in primary cells from infected patients using splice site-specific quantitative RT-PCR. The results indicated a two-phase kinetics with the tax/rex mRNA preceding expression of other viral transcripts. Analysis of mRNA compartmentalization in cells transfected with HTLV-1 molecular clones demonstrated the strict Rex-dependency of the two-phase kinetics and revealed strong nuclear retention of HBZ mRNAs, supporting their function as noncoding transcripts. Mathematical modeling underscored the importance of a delay between the functions of Tax and Rex, which was supported by experimental evidence of the longer half-life of Rex. These data provide evidence for a temporal pattern of HTLV-1 expression and reveal major differences in the intracellular compartmentalization of HTLV-1 transcripts.

Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors.

Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)-infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1-specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.

Human T-lymphotropic virus type 1-induced CC chemokine ligand 22 maintains a high frequency of functional FoxP3+ regulatory T cells.

We recently reported that human T-lymphotropic virus type 1 (HTLV-1) infection is accompanied by a high frequency of CD4(+)FoxP3(+) cells in the circulation. In asymptomatic carriers of HTLV-1 and in patients with HTLV-1-associated inflammatory and malignant diseases, a high FoxP3(+) cell frequency correlated with inefficient cytotoxic T cell-mediated killing of HTLV-1-infected cells. In adult T cell leukemia/lymphoma (ATLL), the FoxP3(+) population was distinct from the leukemic T cell clones. However, the cause of the increase in FoxP3(+) cell frequency in HTLV-1 infection was unknown. In this study, we report that the plasma concentration of the chemokine CCL22 is abnormally high in HTLV-1-infected subjects and that the concentration is strongly correlated with the frequency of FoxP3(+) cells, which express the CCL22 receptor CCR4. Further, we show that CCL22 is produced by cells that express the HTLV-1 transactivator protein Tax, and that the increased CCL22 enhances the migration and survival of FoxP3(+) cells in vitro. Finally, we show that FoxP3(+) cells inhibit the proliferation of ex vivo, autologous leukemic clones from patients with ATLL. We conclude that HTLV-1-induced CCL22 causes the high frequency of FoxP3(+) cells observed in HTLV-1 infection; these FoxP3(+) cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.

FoxP3+ regulatory T cells are distinct from leukemia cells in HTLV-1-associated adult T-cell leukemia.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). It has been postulated that ATLL cells might act as regulatory T cells (T(regs)) which, in common with ATLL cells, express both CD25 and FoxP3, and so contribute to the severe immune suppression typical of ATLL. We report here that the frequency of CD25(+) cells varied independently of the frequency of FoxP3(+) cells in both a cross-sectional study and in a longitudinal study of 2 patients with chronic ATLL. Furthermore, the capacity of ATLL cells to suppress proliferation of heterologous CD4(+)CD25(-) cells correlated with the frequency of CD4(+) FoxP3(+) cells but was independent of CD25 expression. Finally, the frequency of CD4(+)FoxP3(+) cells was inversely correlated with the lytic activity of HTLV-1-specific CTLs in patients with ATLL. We conclude that ATLL is not a tumor of FoxP3(+) regulatory T cells, and that a population of FoxP3(+) cells distinct from ATLL cells has regulatory functions and may impair the cell-mediated immune response to HTLV-1 in patients with ATLL.

The immune control of HTLV-1 infection: selection forces and dynamics.

Cytotoxic T lymphocytes (CTLs) play a central role in the protective immune response to human T-lymphotropic virus 1 (HTLV-1). Here we consider two questions. First, what determines the strength of an individual's HTLV-1-specific CTL response? Second, what controls the rate of expression of HTLV-1 in vivo, which is greater in patients with HAM/TSP than in asymptomatic carriers with the same proviral load? Recent evidence shows that FoxP3+CD4+ T cells are abnormally frequent in HTLV-1 infection, and the frequency of these cells is inversely correlated with the rate of CTL lysis of HTLV-1-infected cells, suggesting that FoxP3+CD4+ cell frequency is an important determinant of the outcome of HTLV-1 infection. There is also new evidence that the rate of expression of HTLV-1 in vivo is associated with the transcriptional activity of the flanking host genome. We suggest that the frequencies of HTLV-1-infected T cell clones in vivo are determined by a dynamic balance between positive and negative selection forces that differ among the clones.

High frequency of CD4+FoxP3+ cells in HTLV-1 infection: inverse correlation with HTLV-1-specific CTL response.

Evidence from population genetics, gene expression microarrays, and assays of ex vivo T-cell function indicates that the cytotoxic T lymphocyte (CTL) response to human T-lymphotropic virus type 1 (HTLV-1) controls the level of HTLV-1 expression and the proviral load. The rate at which CTLs kill autologous HTLV-1-infected lymphocytes differs significantly among infected people, but the reasons for such variation are unknown. Here, we demonstrate a strong negative cor-relation between the frequency of CD4(+)FoxP3(+) Tax(-) regulatory T cells (T(regs)) in the circulation and the rate of CTL-mediated lysis of autologous HTLV-1-infected cells ex vivo. We propose that the frequency of CD4(+)FoxP3(+) Tax(-) T(regs) is one of the chief determinants of the efficiency of T cell-mediated immune control of HTLV-1.

Breast tumor cell soluble factors induce monocytes to produce angiogenic but not angiostatic CXC chemokines.

Tumor cells are known to interact closely with nontumoral infiltrating cells in order to grow and proliferate. Monocyte-derived cells constitute a major component of the tumoral infiltrate and a high level of these cells has been associated with increased tumor growth and poor prognosis in patients with breast cancer. For their growth and metastatic propagation, solid tumors are dependant on angiogenesis and accumulated evidences suggest that monocyte-derived cells could also play an important role in this phenomenon. However, the precise nature of proangiogenic factors secreted by these cells in breast carcinomas, and their direct influence on vessel formation, has not been determined. In the present study, we show that soluble factors secreted by breast tumor cells induce monocytes to produce a variety of proangiogenic CXC chemokines without secretion of angiostatic CXC chemokines. Using in vitro tubule formation in Matrigel, we demonstrated that the CXC chemokines secreted by MTSs (monocytes cultured with tumor cell supernatants) were able to induce microvessel formation. The profile of secreted CXC chemokines was characteristic for each tumor cell line or fresh tumor cells. This last result points out that a precise profiling of secreted proangiogenic factors inside the tumor, by tumor cells themselves or tumor-infiltrating monocyte-derived cells, is important for a precise targeting of therapeutic agents against neovascularization.

Forefront news in immunology from France: annual meeting of the French Society of Immunologists.

The annual meeting of the Société Française d'immunologie (SFI) took place in Strasbourg 27-29th November 2002. The following is a brief synopsis of the key points from presentations in the plenary sessions and symposia, and demonstrates the diversity of subjects addressed in the course of this conference.