Adenosine receptor A2a blockade by caffeine increases IFN-gamma production in Th1 cells from patients with rheumatoid arthritis.

OBJECTIVE: Studies indicate that caffeine uptake may be a risk factor for rheumatoid arthritis (RA), but a definitive link between caffeine consumption and RA has not been established. This study aimed to investigate the interplay between caffeine, adenosine receptor A2a, and interferon-γ (IFN-γ) production in CD4+ T cells from RA patients. METHOD: Peripheral blood mononuclear cells were obtained from the peripheral blood of healthy individuals and patients with RA. CD4+ T cells were isolated using the magnetic activated cell sorting technique and cultured in vitro with caffeine or mock control. In addition, adenosine was used as a competitive inhibitor of caffeine. After 48 h, expression of IFN-γ and interleukin-17 (IL-17) was analysed by flow cytometry. Ex vivo expression levels of adenosine receptor A2a were also assessed. RESULTS: Caffeine promoted IFN-γ production in Th1 cells in vitro. Significantly higher concentrations of caffeine were required to increase IFN-γ levels in Th1 cells from healthy individuals compared to Th1 cells from patients with RA. Moreover, ex vivo levels of adenosine receptor A2a expression on CD4+ T cells were significantly higher in RA than in healthy individuals. Caffeine-driven IFN-γ production was completely reversed by adenosine, a competitive agonist of adenosine receptor A2a. In contrast to IFN-γ, production of IL-17 was not affected by caffeine. CONCLUSION: Caffeine promotes IFN-γ production in Th1 cells from RA patients in vitro by competitive inhibition of adenosine receptor A2a. Excessive coffee consumption could contribute to T-cell activation and inflammation in RA.

Comprehensive evaluation of published gene expression prognostic signatures for biomarker-based lung cancer clinical studies.

Background: A more accurate prognosis for non-small-cell lung cancer (NSCLC) patients could aid in the identification of patients at high risk for recurrence. Many NSCLC mRNA expression signatures claiming to be prognostic have been reported in the literature. The goal of this study was to identify the most promising mRNA prognostic signatures in NSCLC for further prospective clinical validation. Experimental design: We carried out a systematic review and meta-analysis of published mRNA prognostic signatures for resected NSCLC. The prognostic performance of each signature was evaluated via a meta-analysis of 1927 early stage NSCLC patients collected from 15 studies using three evaluation metrics (hazard ratios, concordance scores, and time-dependent receiver-operating characteristic curves). The performance of each signature was then evaluated against 100 random signatures. The prognostic power independent of clinical risk factors was assessed by multivariate Cox models. Results: Through a literature search, we identified 42 lung cancer prognostic signatures derived from genome-wide expression profiling analysis. Based on meta-analysis, 25 signatures were prognostic for survival after adjusting for clinical risk factors and 18 signatures carried out significantly better than random signatures. When analyzing histology types separately, 17 signatures and 8 signatures are prognostic for adenocarcinoma and squamous cell lung cancer, respectively. Despite little overlap among published gene signatures, the top-performing signatures are highly concordant in predicted patient outcomes. Conclusions: Based on this large-scale meta-analysis, we identified a set of mRNA expression prognostic signatures appropriate for further validation in prospective clinical studies.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.

Renal Transplantation With Final Allocation Based on the Virtual Crossmatch.

Solid phase immunoassays (SPI) are now routinely used to detect HLA antibodies. However, the flow cytometric crossmatch (FCXM) remains the established method for assessing final donor-recipient compatibility. Since 2005 we have followed a protocol whereby the final allocation decision for renal transplantation is based on SPI (not the FCXM). Here we report long-term graft outcomes for 508 consecutive kidney transplants using this protocol. All recipients were negative for donor-specific antibody by SPI. Primary outcomes are graft survival and incidence of acute rejection within 1 year (AR <1 year) for FCXM+ (n = 54) and FCXM- (n = 454) recipients. Median follow-up is 7.1 years. FCXM+ recipients were significantly different from FCXM- recipients for the following risk factors: living donor (24% vs. 39%, p = 0.03), duration of dialysis (31.0 months vs. 13.5 months, p = 0.008), retransplants (17% vs. 7.3%, p = 0.04), % sensitized (63% vs. 19%, p = 0.001), and PRA >80% (20% vs. 4.8%, p = 0.001). Despite these differences, 5-year actual graft survival rates are 87% and 84%, respectively. AR <1 year occurred in 13% FCXM+ and 12% FCXM- recipients. Crossmatch status was not associated with graft outcomes in any univariate or multivariate model. Renal transplantation can be performed successfully, using SPI as the definitive test for donor-recipient compatibility.

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

BACKGROUND: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality--a single institution experience.

Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n = 4), stable disease (n = 10), partial remission (n = 20) and progressive disease (n = 6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16 × 10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.

Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer.

BACKGROUND: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated. PATIENTS AND METHODS: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m(2) Q3W)/carboplatin (AUC 6 mg min/ml Q3W). RESULTS: The trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68-1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74-1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1-42.7) and 43.3% (30.6-56.8), respectively; risk ratio 0.676 (95% CI 0.41-1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. CONCLUSIONS: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.

"For a man to go to hospital, then that would be his last option": A qualitative study exploring men's experiences, perceptions and healthcare needs in the implementation of Universal Health Coverage in Kenya.

The achievement of Universal Health Coverage (UHC) requires equitable access and utilization of healthcare services across all population groups, including men. However, men often face unique barriers that impede their engagement with health systems which are influenced by a myriad of socio-cultural, economic, and systemic factors. Therefore, understanding men's perspectives and experiences is crucial to identifying barriers and facilitators to their healthcare-seeking behaviour under UHC initiatives. This qualitative study sought to explore men's perceptions, experiences, healthcare needs and potential strategies to inform an impartial implementation of Universal Health Coverage (UHC) in Kenya. The study employed a qualitative research design to investigate men's healthcare experiences in 12 counties across Kenya. Thirty focus group discussions involving 296 male participants were conducted. Men were purposively selected and mobilized through the support of health facility-in-charges, public health officers, and community health extension workers. Data was coded according to emergent views and further categorized thematically into three main domains (1) Perspectives and experiences of healthcare access (2) Socio-cultural beliefs and societal expectations (3) Desires and expectations of health systems. Findings revealed complex sociocultural, economic, and health system factors that influenced men's healthcare experiences and needs which included: masculinity norms and gender roles, financial constraints and perceived unaffordability of services, lack of male-friendly and gender-responsive healthcare services, confidentiality concerns, and limited health literacy and awareness about available UHC services. Our study has revealed a disconnect between men's needs and the current healthcare system. The expectations concerning masculinity further exacerbate the problem and exclude men further hindering men's ability to receive appropriate care. This data provides important considerations for the development of comprehensive and gender-transformative approaches challenging harmful masculine norms, pushing for financial risk protection mechanisms and gender-responsive healthcare delivery attuned to the unique needs and preferences of men.

Baseline tumour measurements predict survival in advanced non-small cell lung cancer.

BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.

A novel HLA allele derived from a likely DRB1/DRB3 gene conversion event: HLA-DRB3*01:15.

A novel HLA allele, DRB3*01:15, was likely derived via cis-gene conversion.

Surface charge heterogeneity in amphibole cleavage fragments and asbestos fibers.

Aspect ratio and electrophoretic mobility data for amphibole particles reveal that short fibers and blocky cleavage fragments have a smaller net charge than highly elongated particles. Asbestos fibers and cleavage fragments of the same dimensions exhibit the same net negative surface charge but positively charged ends and negatively charged lateral surfaces.

Identification of the protein encoded by the E6 transforming gene of bovine papillomavirus.

Papillomaviruses (PV) contain several conserved genes that may encode nonstructural proteins; however, none of these predicted gene products have been identified. Papillomavirus E6 genes are retained and expressed as RNA in PV-associated human and animal carcinomas and cell lines. This suggests that the E6 gene product may be important in the maintenance of the malignant phenotype. The E6 open reading frame of the bovine papillomavirus (BPV) genome has been identified as one of two BPV genes that can independently transform mouse cells in vitro. A polypeptide encoded by this region of BPV was produced in a bacterial expression vector and used to raise antisera. The antisera specifically immunoprecipitated the predicted 15.5-kilodalton BPV E6 protein from cells transformed by the E6 gene. The E6 protein was identified in both the nuclear and membrane fractions of these transformed cells.

MALDI-TOF "fingerprint" phospholipid mass spectra allow the differentiation between ruminantia and feloideae spermatozoa.

The detailed comparative analysis of sperm lipids could essentially contribute to a better understanding of membrane function in the context of fertilization and, moreover, of sperm preservation. The application of sensitive analytical methods is particularly necessary for endangered species as the available amount of spermatozoa (and, accordingly, extractable lipids) is strongly limited. It will be shown that matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a fast, simple and sensitive method for the determination of the phospholipid composition of spermatozoa from several ruminantia (cattle, roe deer, Klipspringer) and feloideae species (domestic cat, Siberian tiger, fosa). Characteristic "fingerprints" are obtained from the positive ion spectra that allow the differentiation between both animal groups. In contrast to the lipid extracts of ruminantia spermatozoa which predominantly contain ether lipids including essential amounts of plasmalogens, the more complex phospholipid composition of feloideae spermatozoa is clearly dominated by diacyl phospholipids and contains only marginal amounts of plasmalogens. It will also be shown that the lipid compositions of ejaculated, electroejaculated and cauda epididymal spermatozoa of the same species are very similar and give comparable data. Therefore, the analysis of ejaculated spermatozoa is not an absolute must.

Phospholipid compositions of sera and synovial fluids from dog, human and horse: a comparison by 31P-NMR and MALDI-TOF MS.

Alterations of the phospholipid (PL) compositions of body fluids are assumed to be indicative of inflammatory diseases, e.g. rheumatoid arthritis (RA). Recently, we have shown that particularly the phosphatidylcholine/lysophosphatidylcholine (PC/LPC) ratio determined in human synovial fluids (SF) and sera represents a reliable measure of the inflammatory state in RA patients. However, it is not yet clear to what extent the PC/LPC ratio is also affected by nutrition habits. In the present study, the PL and the corresponding acyl chain compositions of human body fluids (SF and serum of RA patients as well as serum from healthy volunteers) are compared with those of two other mammalian species (horses and dogs suffering from degenerative joint diseases as well as healthy controls) by high-resolution 31P-nuclear magnetic resonance (NMR) spectroscopy and matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS). The most important result of this study is that the PL compositions of SF and serum of horse and dog are comparable with those of human body fluids. Compared with humans, however, the horse body fluid contains less PCs with highly unsaturated arachidonoyl residues, while that of dogs possesses the highest content of arachidonoyl-containing PC. These species-related differences stem primarily from different nutrition habits (meat vs. plants).

In vitro supplementation with unsaturated fatty acids improves boar sperm viability after storage at 6 °C.

Liquid preservation of the cold-sensitive boar sperm at a lesser temperature than the standard 17 °C would reduce bacterial growth and minimize the use of antibiotics. There was assessment, therefore, of the capacity of individual fatty acids bound to fatty acid free BSA to improve sperm survival at 6 °C because oxidative stress and lipid degradation are prominent detrimental factors. Different effects of the fatty acids were observed. Supplementation with naturally occurring fatty acids (linolenic, linoleic, oleic, palmitoleic acid), which may become metabolically incorporated into sperm lipids, increased the number of motile and progressively motile sperm after 2 days of storage during a thermo-resistance test (5 h at 38 °C) to that of control samples preserved at 17 °C in pure Beltsville Thawing Solution. With the exception of linolenic acid, all naturally occurring fatty acids enhanced the number of sperm with active mitochondria after 3 days of storage. Palmitoleic acid was the most effective supplement with effects already present when sperm were re-warmed for 30 min after 2 and 7 days of storage. The non-endogenous, non-integrated timnodonic acid (20:5) had no effect on sperm variables. Because the application of individual fatty acids attached to BSA had differing effects in preserving boar sperm at 6 °C, the use of combinations of fatty acids could be more efficacious than with use of natural lipid supplements for low temperature preservation of sperm.

Efficacy of a Carrageenan gel Against Transmission of Cervical HPV (CATCH): interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial.

OBJECTIVES: To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. METHODS: We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. RESULTS: Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9-13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45-0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. CONCLUSIONS: Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

The best from East and West? Acupuncture and medical training therapy as monotherapies or in combination for adult patients with episodic and chronic tension-type headache: study protocol for a randomized controlled trial.

BACKGROUND: This study aims to evaluate the feasibility and efficacy of a complex health intervention, based on the combination of conventional Western medicine and traditional Chinese medicine (TCM), in an outpatient department of a university hospital for patients with frequent episodic or chronic tension-type headaches. METHODS/DESIGN: This is a prospective randomized controlled pilot study with four balanced treatment arms (usual care, acupuncture, training, and training plus acupuncture). Each arm will have 24 patients. After the initial screening examination and randomization, a 6-week treatment period follows, with treatment frequencies decreasing at 2-week intervals. After completion of the intervention, two follow-up evaluations will be performed 3 and 6 months after the start of treatment. At predefined times, the various outcomes (pain intensity, health-related quality of life, pain duration, autonomic regulation, and heart rate variability) as well as the participants' acceptance of the complex treatment will be evaluated with valid assessment instruments (Migraine Disability Assessment, PHQ-D, GAD-7, and SF-12) and a headache diary. The acupuncture treatment will be based on the rules of TCM, comprising a standardized combination of acupuncture points and additional points selected according to individual pain localization. The training therapy comprises a combination of strength training, endurance training, and training to improve flexibility and coordination. Besides descriptive analyses of the samples, their comparability will be assessed using an analysis of variance (ANOVA) or chi-squared tests. Analyses will be performed on an intention-to-treat basis. Potential interaction effects will be calculated using a repeated-measures ANOVA to test the primary and secondary hypotheses. In supplementary analyses, the proportion of treatment responders (those with a 50% reduction in the frequency of pain episodes) will be determined for each treatment arm. DISCUSSION: This trial may provide evidence for the additive effects of acupuncture and medical training therapy as a combination treatment and may scientifically support the implementation of this complex health intervention. TRIAL REGISTRATION: Registered on 11 Feburary 2019. German Clinical Trials Register, DRKS00016723.

NMDA receptors amplify calcium influx into dendritic spines during associative pre- and postsynaptic activation.

Long-term potentiation (LTP) of synaptic strength can be induced by synchronous pre- and postsynaptic activation, and a rise in postsynaptic calcium is essential for induction of LTP. Calcium can enter through both voltage-dependent Ca2+ channels and NMDA-type glutamate receptors, but the relative contributions of these pathways is not known. We have examined this issue in layer V cortical pyramidal neurons, using focal flash photolysis of caged glutamate to mimic synaptic input and two-photon, laser-scanning microscopy to measure calcium levels in dendritic spines. Most of the calcium entry in response to glutamate alone was via voltage-dependent Ca2+ channels, and NMDA receptors accounted for less than 20% of total Ca2+ entry. When glutamate was paired with postsynaptic action potentials, however, the NMDA-receptor-dependent component was selectively amplified. The same is likely to occur during paired physiological pre- and postsynaptic activation, providing a mechanism for the input specificity and Hebbian behavior of LTP.

Conjugation of a self-antigen to papillomavirus-like particles allows for efficient induction of protective autoantibodies.

High avidity and long-lasting autoantibodies to a self-polypeptide (TNF-alpha) were generated after parenteral vaccination of mice with low doses of virus-like particle-based (VLP-based) vaccines that were constructed by linking mouse TNF-alpha peptides to the surface of papillomavirus VLPs. High-titer autoantibodies were induced with or without coadministration of potent conventional adjuvants, but were enhanced by coadministration of CFA. Compared with immunization with the fusion protein alone, attachment to VLPs increased autoantibody titers 1,000-fold. A comparison of Ab responses against the self (TNF-alpha) and foreign components of the fusion protein showed that VLP conjugation abrogated the ability of the humoral immune system to distinguish between self and foreign. Similar levels of IgM were detected to self and foreign epitopes regardless of the assembly state of the antigen, suggesting that conjugation of self-peptides to VLPs promotes survival or expansion of mature autoreactive B cells. In a mouse model, vaccination with conjugated particles inhibited development of type II collagen-induced arthritis. Together, these results suggest a potentially flexible method to efficiently generate autoantibodies against specific self-proteins that mediate arthritis and other diseases.