Current status of pediatric intestinal transplantation in the United States.

PURPOSE OF REVIEW: The present review aims to describe in detail the characteristics, outcomes, and recent trends in the field of pediatric intestinal transplantation in the United States. It will examine the route cause and future implications of these developments. The review will draw from recent publications in the field, the Intestinal Transplant Registry, and contemporary data from large U.S. single centers. RECENT FINDINGS: More than 1500 pediatric intestinal transplants have been performed in the United States since 1985, however, over the past decade there have been fewer than 50 transplants/year nationwide. This trend is largely a result of stagnant long-term ITx outcomes and advancements in intestinal rehabilitation programs. Nationally the overall 1-year and 5-year graft survival are 68 and 50% respectively, whereas certain high-volume centers have experienced significantly better results. Sepsis is the leading cause of death following pediatric ITx, whereas rejection is the leading cause of graft loss. Chronic kidney disease and posttransplant lymphoproliferative disorder are significant and relatively prevalent long-term complications. The majority of pediatric ITx recipients receive T-cell depleting induction agents and are on Tacrolimus-based immunosuppression. Most recipient are off parenteral nutrition, but may require supplemental tube feeds. Many pediatric ITx recipients require special education, and in certain domains some report lower health related quality of life. SUMMARY: As intestinal rehabilitation has improved in the modern era, the volume of pediatric ITx in the United States has decreased. Although pediatric ITx results have room for improvement nationwide, successful outcomes have been reported at experienced American centers.

Treatment delays for patients with new-onset rheumatoid arthritis presenting to an Australian early arthritis clinic.

BACKGROUND: Early treatment ensures optimal outcomes in rheumatoid arthritis (RA) yet there are limited data in Australia quantifying treatment delays in clinical practice. AIMS: To quantify treatment delays in new RA patients and to explore factors influencing delay and resultant patient outcomes. METHODS: Data were obtained for 88 patients presenting with a new diagnosis of RA to an early arthritis clinic (EAC) in Australia between 2008 and 2015. Date and details of symptom onset, initial general practitioner (GP) presentation, GP referral and review at EAC were collected. Patient demographics and clinical features were analysed for outcomes and features predictive of delay. RESULTS: Median overall delay from symptom onset to rheumatology review was 26.4 weeks. Patient delay (8.7 weeks) was the longest delay and predicted overall delay. Delays in GP referral and time to EAC review were 4 and 8.4 weeks respectively. Increased overall delay was predicted by lower fatigue and disease activity scores (DAS28) and increased tender joint counts (TJC). Patient delay was increased by socioeconomic disadvantage. Increased GP delay was associated with lower DAS28 and higher TJC and ESR. Patients seen within 16 weeks had greater improvement in DAS28 and probability of remission at 6 months. CONCLUSIONS: In this Australian EAC setting, patient delay was the greatest contributor to RA treatment delay. Delays in treatment were associated with lower disease severity and socioeconomic disadvantage. Remission was more likely after prompt initiation of treatment.

Blast-related mild traumatic brain injury: a Bayesian random-effects meta-analysis on the cognitive outcomes of concussion among military personnel.

Throughout their careers, many soldiers experience repeated blasts exposures from improvised explosive devices, which often involve head injury. Consequentially, blast-related mild Traumatic Brain Injury (mTBI) has become prevalent in modern conflicts, often occuring co-morbidly with psychiatric illness (e.g., post-traumatic stress disorder [PTSD]). In turn, a growing body of research has begun to explore the cognitive and psychiatric sequelae of blast-related mTBI. The current meta-analysis aimed to evaluate the chronic effects of blast-related mTBI on cognitive performance. A systematic review identified 9 studies reporting 12 samples meeting eligibility criteria. A Bayesian random-effects meta-analysis was conducted with cognitive construct and PTSD symptoms explored as moderators. The overall posterior mean effect size and Highest Density Interval (HDI) came to d = -0.12 [-0.21, -0.04], with executive function (-0.16 [-0.31, 0.00]), verbal delayed memory (-0.19 [-0.44, 0.06]) and processing speed (-0.11 [-0.26, 0.01]) presenting as the most sensitive cognitive domains to blast-related mTBI. When dividing executive function into diverse sub-constructs (i.e., working memory, inhibition, set-shifting), set-shifting presented the largest effect size (-0.33 [-0.55, -0.05]). PTSD symptoms did not predict cognitive effects sizes, ß PTSD = -0.02 [-0.23, 0.20]. The results indicate a subtle, but chronic cognitive impairment following mTBI, especially in set-shifting, a relevant aspect of executive attention. These findings are consistent with past meta-analyses on multiple mTBI and correspond with past neuroimaging research on the cognitive correlates of white matter damage common in mTBI. However, all studies had cross-sectional designs, which resulted in universally low quality ratings and limited the conclusions inferable from this meta-analysis.

White matter abnormalities and working memory impairment in systemic lupus erythematosus.

OBJECTIVE/BACKGROUND: Many patients with systemic lupus erythematosus (SLE) have working memory deficits. Few studies have evaluated working memory performance and neurometabolite profile using magnetic resonance spectroscopy in SLE. METHODS: We gave the Paced Auditory Serial Addition Test (PASAT), a measure of working memory, to 73 patients with SLE. We calculated total score, dyads, chunking, and cognitive fatigue. Using magnetic resonance spectroscopy, we determined the ratio of choline to creatine (Ch/Cr) in normal-looking right and left frontal lobe white matter. RESULTS: Twenty-nine percent of patients showed impaired working memory on the PASAT. Total PASAT score inversely correlated with right and left frontal white matter Ch/Cr. Left frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. Right frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. There was no relationship between cognitive fatigue and either left or right frontal white matter Ch/Cr. Longer disease duration was associated with higher left frontal white matter Ch/Cr. Correlations remained significant when we considered disease duration and left frontal white matter Ch/Cr against total PASAT score and total dyads. CONCLUSIONS: Patients with SLE were impaired on the PASAT. Lower total PASAT score and fewer dyads correlated with higher left frontal microstructural white matter damage, while cognitive fatigue did not. This pattern suggests that early white matter damage interferes with working memory in SLE and provides further insight into the neurobiological basis of mild cognitive dysfunction related to microstructural white matter injury.

A Systematic Review of the Outcomes of Microsurgical Toe Transfer for Metacarpal and Metacarpal-Like Hand Deformity.

Background: Thumb and multiple finger amputations may result in a metacarpal and a metacarpal-like hand deformity. Toe-to-hand transfer is a recognised treatment strategy for this deformity but has risks and is resource intensive. The aim of this study is to conduct a systematic review of the outcomes of toe-to-hand transfer for traumatic metacarpal and metacarpal-like hand deformity in adult patients. Methods: Multi-database searching with index and free text terms, duplicate standardised screening and extraction, and quality assessment was performed. The inclusion and exclusion criteria were prespecified. We included any randomised controlled trials, cohort studies, case-control studies, as well as interrupted time series, before and after intervention studies. Results: Screening of 548 articles yielded 20 studies eligible that included 19 retrospective observational studies and one before and after intervention study. A total of 171 patients underwent 274 toe transfers for metacarpal and metacarpal-like hand deformity. No study compared toe-transfer to a control group or to a prosthesis. The before and after intervention study demonstrated significant improvement in activities of daily living, work, aesthetics and satisfaction. Additionally, no significant donor site morbidity occurred in the heterogenous sample. Outcomes from remaining studies at risk of bias suggest that those with a lesser severity of injury and at least two toe transfers score higher in functional tests and scoring systems. Conclusions: There is limited confidence in the effectiveness of toe transfer for metacarpal and metacarpal-like hand deformity. The available evidence indicates that toe transfer(s) may restore acceptable function permitting activities of daily living, return to original or sedentary occupation and affords satisfaction. Level of Evidence: Level III (Therapeutic).

Delivering the CRISPR/Cas9 system for engineering gene therapies: Recent cargo and delivery approaches for clinical translation.

Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR/Cas9) has transformed our ability to edit the human genome selectively. This technology has quickly become the most standardized and reproducible gene editing tool available. Catalyzing rapid advances in biomedical research and genetic engineering, the CRISPR/Cas9 system offers great potential to provide diagnostic and therapeutic options for the prevention and treatment of currently incurable single-gene and more complex human diseases. However, significant barriers to the clinical application of CRISPR/Cas9 remain. While in vitro, ex vivo, and in vivo gene editing has been demonstrated extensively in a laboratory setting, the translation to clinical studies is currently limited by shortfalls in the precision, scalability, and efficiency of delivering CRISPR/Cas9-associated reagents to their intended therapeutic targets. To overcome these challenges, recent advancements manipulate both the delivery cargo and vehicles used to transport CRISPR/Cas9 reagents. With the choice of cargo informing the delivery vehicle, both must be optimized for precision and efficiency. This review aims to summarize current bioengineering approaches to applying CRISPR/Cas9 gene editing tools towards the development of emerging cellular therapeutics, focusing on its two main engineerable components: the delivery vehicle and the gene editing cargo it carries. The contemporary barriers to biomedical applications are discussed within the context of key considerations to be made in the optimization of CRISPR/Cas9 for widespread clinical translation.

A Coordinated Multi-study Analysis of the Longitudinal Association Between Handgrip Strength and Cognitive Function in Older Adults.

OBJECTIVE: Handgrip strength, an indicator of overall muscle strength, has been found to be associated with slower rate of cognitive decline and decreased risk for cognitive impairment and dementia. However, evaluating the replicability of associations between aging-related changes in physical and cognitive functioning is challenging due to differences in study designs and analytical models. A multiple-study coordinated analysis approach was used to generate new longitudinal results based on comparable construct-level measurements and identical statistical models and to facilitate replication and research synthesis. METHODS: We performed coordinated analysis on 9 cohort studies affiliated with the Integrative Analysis of Longitudinal Studies of Aging and Dementia (IALSA) research network. Bivariate linear mixed models were used to examine associations among individual differences in baseline level, rate of change, and occasion-specific variation across grip strength and indicators of cognitive function, including mental status, processing speed, attention and working memory, perceptual reasoning, verbal ability, and learning and memory. Results were summarized using meta-analysis. RESULTS: After adjustment for covariates, we found an overall moderate association between change in grip strength and change in each cognitive domain for both males and females: Average correlation coefficient was 0.55 (95% CI = 0.44-0.56). We also found a high level of heterogeneity in this association across studies. DISCUSSION: Meta-analytic results from nine longitudinal studies showed consistently positive associations between linear rates of change in grip strength and changes in cognitive functioning. Future work will benefit from the examination of individual patterns of change to understand the heterogeneity in rates of aging and health-related changes across physical and cognitive biomarkers.

Systematic Review of Pulmonary Function and Cognition in Aging.

BACKGROUND: Substantial research is dedicated to understanding the aging-related dynamics among individual differences in level, change, and variation across physical and cognitive abilities. Evaluating replicability and synthesizing findings has been limited by differences in measurements, samples, study design, and statistical analyses that confound between-person differences with within-person changes. Here, we systematically reviewed longitudinal results on the aging-related dynamics linking pulmonary function and cognitive performance. METHODS: Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines were used to systematically review longitudinal studies of pulmonary function and cognition. RESULTS: Only four studies thoroughly investigating cognitive and pulmonary longitudinal associations (three or more measurement occasions) were identified. Expanded review criteria identified three studies reporting two measurement occasions, and seven studies reporting one measurement of pulmonary function or cognition and two or more measurements of the other. We identified numerous methodological quality and risk for bias issues across studies. CONCLUSIONS: Despite documented correlational associations between pulmonary function and cognition, these results show there is very limited research thoroughly investigating their longitudinal associations. This highlights the need for longitudinal data, rigorous methodological design including key covariates, and clear communication of methods and analyses to facilitate replication across an array of samples. We recommend systematic study of outcome measures and covariates, inclusion of multiple measures (e.g., peak expiratory flow, forced expiratory volume in 1 s, and forced vital capacity), as well as application of the same analytic approach across multiple datasets.

Contributing Towards a Cultural Neuropsychology Assessment Decision-Making Framework: Comparison of WAIS-IV Norms from Colombia, Chile, Mexico, Spain, United States, and Canada.

OBJECTIVE: Test and normative data selection in cross-cultural neuropsychology remain a complex issue. Despite growing awareness, more studies and instruments are needed to adequately address the impact of cultural factors, such as quantity and quality of education. In this study, we examine the interpretive effects of applying six relevant WAIS-IV norms to a Colombian sample. METHOD: A sample of 305 highly educated Colombian corporate executives completed the WAIS-IV. Data were scored using norms from Colombia, Chile, Mexico, Spain, United States, and Canada and scores were compared using ANOVA. Additionally, a comparative sociodemographic framework was established to contextualize our sample to the standardization samples and populations of the six countries. RESULTS: Colombian and Chilean norms yielded systematically similar FSIQ/Index scores (mean range = 117-121), while incrementally lower scores were found with norms from Mexico (-3-9 points), Spain (-3-11 points), USA (-8-13 points), and Canada (-11-18 points). Verbal scores differed, with highest scores obtained with Mexican and Spanish norms. Working memory and processing speed scores had the lowest score agreement across norms. CONCLUSIONS: Although the Chilean norms are more frequently used in Colombia, the recently developed Colombian norms appear optimal for our sample; the scores do not have meaningful differences with those obtained with Chilean norms and offer local population representation fidelity. Mexican, Spanish, US, and Canadian norms underestimated WAIS-IV scores and distorted the sample's score distribution. Finally, verbal scores highlight potential education representation within Spanish and Mexican norms, while working memory and processing speed scores suggest cultural nuances likely captured within different norms.

A Multi-study Coordinated Meta-analysis of Pulmonary Function and Cognition in Aging.

BACKGROUND: Substantial research is dedicated to understanding the aging-related dynamics among individual differences in level, change, and variation across physical and cognitive abilities. Evaluating replicability and synthesizing these findings has been limited by differences in measurements and samples, and by study design and statistical analyses confounding between-person differences with within-person changes. In this article, we conducted a coordinated analysis and summary meta-analysis of new results on the aging-related dynamics linking pulmonary function and cognitive performance. METHODS: We performed coordinated analysis of bivariate growth models in data from 20,586 participants across eight longitudinal studies to examine individual differences in baseline level, rate of change, and occasion-specific variability in pulmonary and cognitive functioning. Results were summarized using meta-analysis. RESULTS: We found consistent but weak baseline and longitudinal associations in levels of pulmonary and cognitive functioning, but no associations in occasion-specific variability. CONCLUSIONS: Results provide limited evidence for a consistent link between simultaneous changes in pulmonary and cognitive function in a normal aging population. Further research is required to understand patterns of onset of decline and differences in rates of change within and across physical and cognitive functioning domains, both within-individuals and across countries and birth cohorts. Coordinated analysis provides an efficient and rigorous approach for replicating and comparing results across independent longitudinal studies.

Derivation, Replication, and Validity Analyses of a Screener for the Behavioral Assessment of Executive Functions in Young Adults.

Ecologically valid indicators of executive functions are designed to capture dysfunction not easily measured in a lab setting. Here, we present two studies on the development and validity analyses of a behavioral screener for executive functions among young adults. In Study 1, we derived a four-factor (problem solving, attentional control, behavioral control, and emotional control) behavioral screener using a sample of 765 individuals. We used invariance analyses to evaluate the screener's measurement reliability across sex. In Study 2, we replicated the screener derivation analyses using an independent sample of 197 undergraduates. To further examine the screener's validity, we evaluated it against a well-known executive functions rating scale. The four-factor model was supported in both samples and analyses provided support for this screener as a valid and reliable measure for everyday executive functions among young adults.

Trajectory of intensive treat-to-target disease modifying drug regimen in an observational study of an early rheumatoid arthritis cohort.

OBJECTIVES: Studies of early rheumatoid arthritis (RA) cohorts have analysed treatment response and prognostic factors at fixed time points. However, in treat-to-target protocols, therapeutic decision-making is dynamic and responsive to disease activity over time. To determine when a minimal residual disease response target should be expected, our primary objective was to identify the time-dependent therapeutic response to combination disease modifying antirheumatic drugs (DMARDs) for 12 months. Our secondary objective determined factors affecting this response trajectory. DESIGN: Observational cohort. SETTING: Treat-to-target early RA clinic in Australian tertiary referral hospital. PARTICIPANTS: We enrolled consecutive patients attending an early arthritis clinic with symptom duration less than 12 months, who were diagnosed with RA for the first time between 2004 and 2008. 101 met these eligibility criteria and data were available at baseline through 12 months. INTERVENTIONS: intensive DMARDs according to a treat-to-target protocol. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured disease activity scores (DAS) at each visit, then analysed therapeutic response and associated factors in a time-dependent fashion over 12 months. RESULTS: The median DAS4vESR of 4.46 at baseline decreased 12 weeks later by 24%, while the proportion with DAS4v ≤ 2.6 increased (p<0.01). DAS4v continued to decrease over 52 weeks. DAS4v reduction of at least -0.45 at 4 weeks was predictive of DAS4v at 28 and 52 weeks. Female gender, current smoking, primary education and an interaction between baseline weight and C reactive protein (CRP) negatively impacted DAS4v reduction over 4 and 52 weeks. Time-varying effects of blood pressure, neutrophils, erythrocyte sedimentation rate and CRP also significantly influenced DAS4v over 52 weeks. CONCLUSIONS: Time-dependent data suggest that the largest reduction of DAS4v to combination DMARDs occurs in the first month of therapy, and this predicts subsequent response. Variables known to impact long-term treatment response in RA also impacted early DAS4v response to combination DMARDs.

Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.

Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.

Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.

AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.

Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.

AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.

Interleukin-1ß produced in response to islet autoantigen presentation differentiates T-helper 17 cells at the expense of regulatory T-cells: Implications for the timing of tolerizing immunotherapy.

OBJECTIVE: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1ß is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1ß production and the response to RelB(lo) DCs in the prediabetic period. RESEARCH DESIGN AND METHODS: We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. RESULTS: Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1ß production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion. CONCLUSIONS: IL-1ß, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1ß/IL-17 checkpoint signals the need for other strategies.

Antigen-specific suppression of established arthritis in mice by dendritic cells deficient in NF-kappaB.

OBJECTIVE: NF-kappaB inhibitors applied to animal models of rheumatoid arthritis (RA) demonstrate the important role of NF-kappaB in the production of mediators of inflammation in the joint and their antiinflammatory effects. Because NF-kappaB is involved in the differentiation, activation, and survival of almost all cells, its prolonged inhibition might have unwanted adverse effects. Therefore, we sought to apply NF-kappaB inhibitors more specifically, targeting dendritic cell (DC) differentiation, in order to influence the outcome of the autoimmune response, rather than to produce a broad antiinflammatory effect. We tested whether DCs treated with the NF-kappaB inhibitor BAY 11-7082 and exposed to arthritogenic antigen would suppress established arthritis in C57BL/6 mice. METHODS: Antigen-induced arthritis was generated in C57BL/6 mice by injection of methylated bovine serum albumin (mBSA). After mBSA challenge, mouse knee joints were injected with antigen-exposed BAY 11-7082-treated DCs or with soluble tumor necrosis factor receptor (sTNFR). Intraarticular injection of interleukin-1 (IL-1) was used to induce disease flare. RESULTS: Inflammation and erosion were suppressed in mice that received mBSA-exposed BAY 11-7082-treated DCs, but not in those that received keyhole limpet hemocyanin-exposed BAY 11-7082-treated DCs. Clinical improvement was dependent on IL-10 and was associated with antigen-specific suppression of the delayed-type hypersensitivity (DTH) reaction and switching of anti-mBSA antibody isotype from IgG2b to IgG1 and IgA. Suppression of the DTH reaction or arthritic disease was not impaired by concomitant administration of sTNFR. Suppression could be reversed with intraarticular administration of IL-1beta and could be restored by a second injection of mBSA-exposed BAY 11-7082-treated DCs. CONCLUSION: BAY 11-7082-treated DCs induce antigen-specific immune suppression in this model of inflammatory arthritis, even after full clinical expression of the disease. Such DCs have potential as antigen-specific therapy for autoimmune inflammatory arthritis, including RA.