IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia.

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14 to 19. We found that IL-33 supplementation in RUPP rats reduces maternal blood pressure and improves the uterine artery resistance index (UARI). In addition to physiological improvements, we found decreased circulating and placental cytolytic Natural Killer cells (cNKs) and decreased circulating, placental, and renal TH17s in IL-33-treated RUPP rats. cNK cell cytotoxic activity also decreased in IL-33-supplemented RUPP rats. Furthermore, renal ROS and placental preproendothelin-1 (PPET-1) decreased in RUPP rats treated with IL-33. These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, renal ROS, and PPET-1 expression. These data suggest that IL-33 may have therapeutic potential in managing PE.NEW & NOTEWORTHY Though decreased IL-33 signaling has been clinically associated with PE, the mechanisms linking this signaling pathway to overall disease pathophysiology are not well understood. This study provides compelling evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction observed in response to placental ischemia, such as in PE. Data presented in this study submit the IL-33 signaling pathway as a possible therapeutic target for the treatment of PE.

Robotic Surgery for Ulcerative Colitis.

Subtotal colectomy (STC) or total proctocolectomy (TPC) and ileal pouch-anal anastomosis (IPAA) performed in two or three stages remain the procedure of choice for patients with ulcerative colitis (UC). Minimally invasive laparoscopic approaches for STC and IPAA have been established for over a decade, having been shown to reduce postoperative pain, length of stay, and improve fertility. However "straight-stick" laparoscopy has ergonomic and visual disadvantages in the pelvis, which may contribute to IPAA failure. The robotic platform was developed to overcome these limitations. Robotic STC is associated with lower conversion rates and earlier return of bowel function with acceptably longer operative time (mean, 28 minutes) than laparoscopic STC. The robotic approach has also been shown in case series to be safe in urgent settings. Robotic IPAA is associated with lower blood loss and length of stay than laparoscopic IPAA. Robotic TPC/IPAA has been shown in small case series to be safe and feasible despite longer operating times.

Characterizing different-flavored e-cigarette solutions from user-reported sensory attributes and appeal.

Scientists and regulators need parsimonious methods of characterizing flavored e-cigarettes which may vary widely in both chemical flavoring constituents and marketing descriptors. This laboratory experiment characterized user-reported appeal and experience of five cross-cutting sensory attributes (sweetness, bitterness, smoothness, harshness, coolness) of 10 common e-cigarette flavors. In a within-subject double-blind single-visit protocol, current nicotine/tobacco product users (N = 119) self-administered a single puff of each e-liquid flavor via a pod-style device and rated its appeal and sensory attributes on 0-100 scales. Custom-manufactured e-liquids, nicotine concentration: M (SD) = 23.4 (0.9) mg/mL, representative of commonly marketed fruit (green apple, strawberry), dessert (dark chocolate, vanilla), mint (peppermint, spearmint), nonmint cooling (menthol, koolada), and tobacco (subtle tobacco, full-flavored tobacco) flavor descriptors were used and their constituents were independently analyzed. Results largely demonstrated that a flavor's sensory attributes concorded with its marketed flavor descriptor. Among the 10 flavors, vanilla was rated sweetest (B[difference vs. mean of 9 other flavors] = 14.44, 95% CI [10.84, 18.03]), full-flavored tobacco was most bitter, B = 8.34, 95% CI [4.73, 11.96], subtle tobacco was most harsh, B = 5.69, 95% CI [1.70, 9.68], and peppermint scored highest in both smoothness, B = 6.98, 95% CI [3.13, 10.82], and coolness, B = 29.25, 95% CI [25.50, 33.01]. Flavors with higher appeal ratings tended to be sweeter, smoother, cooler, and less bitter and harsh. Chemical analysis found numerous flavoring constituents among study products without any clear differentiation of chemicals being present in particular flavor categories, which underscores the utility of using sensory ratings to characterize different-flavored e-cigarettes over and above constituent analyses. Characterizing e-cigarette flavors by subjective sensory attributes may be useful in future research and regulatory activities. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma?

OBJECTIVE: To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. METHODS: A retrospective, single-institution analysis of 413 HCC patients from 1999 to 2009. RESULTS: A total of 413 patients with HCC underwent surgical resection (n = 106) and transplantation (n = 270) or were listed without receiving transplantation (n = 37). Excluding transplanted patients with incidental tumors (n = 50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection versus ITT patients was similar (5-year survival of 53.0% vs 52.0%, not significant). However, for HCC patients with model end-stage liver disease (MELD) scores less than 10 and who radiologically met Milan or UCSF (University of California, San Francisco) criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD score less than 10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n = 26) versus 83.0% and 41.0% for ITT (n = 73, P = 0.036). For those with MELD score less than 10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n = 33) versus 81.0% and 40.0% for ITT (n = 78, P = 0.027). CONCLUSIONS: Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest that surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

Robotic ileocolic resection with intracorporeal anastomosis for Crohn's disease.

The robotic platform can overcome limitations of the laparoscopic approach, particularly in the facilitation of intracorporeal anastomosis creation. We aim to share our institutional experience with robotic ileocolic resection for Crohn's disease (CD) and compare it to a laparoscopic cohort. We identified patients who underwent ileocolic resection for CD with a purely robotic (R) or laparoscopic (L) approach between February 2015 and 2018. Chart review was performed and preoperative, intraoperative, and postoperative data was collected. A total of 47 patients with a mean age of 35.2 years old were identified and 61% were female. Seventy percent [n = 33, (23 females, 69.6%)] of the cases were performed robotically and 30% of the cases [n = 14, (6 females, 42.8%)] were performed laparoscopically. The groups were well matched for age, gender, BMI as well as disease related factors (CD duration; clinical classification and location), perioperative immunosuppression, and surgical history. Time to bowel function was shorter by about 1 day in the robotic group (R: 1.9 ± 0.88 days vs. L: 2.7 ± 0.8 days, p = 0.003). Mean operative time was longer in the robotic group by 51 min and this difference was significant (p = 0.03), however 30.3% of patients underwent ureteral stent placement, which can account for added time in robotic cases. There were less conversions in the robotic group [R: 1(4.3%) vs. L: 1(7%)], but this was not significant. There were no intraoperative complications in either group. Complication (L: 21.4% vs. R: 15.1%, p = 0.605) and reoperation rates (L: 0% vs. R: 3.03%, p = 0.429) were similar. Robotic ileocolic resection for Crohn's disease is as safe and feasible as the laparoscopic approach. This was accomplished with no leaks, major morbidity or mortality and comparable length of stay, with 1 day shorter return of bowel function, and with a lower overall complication rate. The robotic approach offers advantages in Crohn's disease which should be studied further in prospective studies.

Effect of Exposure to e-Cigarettes With Salt vs Free-Base Nicotine on the Appeal and Sensory Experience of Vaping: A Randomized Clinical Trial.

Importance: Alkaline free-base nicotine is bitter and a respiratory irritant. High-nicotine electronic cigarette (e-cigarette) products contain acid additives that change nicotine from a free-base to a protonated salt chemical form, which could improve the sensory experience of vaping, particularly among never smokers unaccustomed to inhaling free-base nicotine. Objective: To determine whether exposure to e-cigarettes with salt vs free-base nicotine formulations improves the appeal and sensory experience of vaping e-cigarettes and whether nicotine formulation effects differ by e-cigarette flavor and ever combustible cigarette smoking status. Design, Setting, and Participants: Single-visit double-blind within-participant randomized clinical trial was conducted in an academic medical center outpatient clinical research facility in Southern California. Participants were 119 individuals with past 30-day e-cigarette or combustible cigarette use aged 21 years or older recruited from November 2019 to March 2020. Interventions: Participants self-administered standardized puffs of each 10 differently flavored e-cigarette solutions using a pod-style device. Each flavor was administered in salt (benzoic acid added) and free-base (no benzoic acid) nicotine formulations with commensurate nicotine concentrations (mean, 23.6 mg/mL). The 20 solutions were administered in randomly assigned sequences. Immediately after puffing each solution, participants rated appeal and sensory attributes. Main Outcomes and Measures: Self-reported appeal (mean of like, dislike [reverse-scored], and willingness to use again ratings) and 4 sensory attributes (sweetness, smoothness, bitterness, and harshness; analyzed individually) on visual analog scales with not at all and extremely anchors (range, 0-100). Results: Of the 119 participants; 39 (32.8%) were female. The mean (SD) age was 42.1 (14.4) years; 105 (88.2%) were ever combustible cigarette smokers, and 66 (55.5%) were current e-cigarette users. Salt vs free-base nicotine formulations produced higher ratings of appeal (salt vs free-base mean difference effect estimate: b = 12.0; 95% CI, 9.9-14.1; P < .001), sweetness (b = 9.3; 95% CI, 7.1-11.4; P < .001), and smoothness (b = 17.4; 95% CI, 15.2-19.6; P < .001) and lower ratings of bitterness (b = -13.3; 95% CI, -15.4 to -11.2; P < .001) and harshness (b = -21.0; 95% CI, -23.2 to -18.7; P < .001). Nicotine formulation effects largely generalized across different flavors and the smoothness-enhancing and harshness-reducing effects of nicotine salt were stronger in never vs ever cigarette smokers. Conclusions and Relevance: In this randomized clinical trial of adult current nicotine or tobacco product users, controlled exposure to e-cigarette puffs with salt vs free-base nicotine formulations appeared to increase product appeal and improve the sensory experience of vaping, particularly among never smokers. Regulatory policies limiting acid additives in e-cigarettes might reduce the appeal of high-nicotine e-cigarettes among populations deterred from vaping e-cigarettes that emit harsh aerosol. Trial Registration: ClinicalTrials.gov Identifier: NCT04399031.

Early experience with urgent robotic subtotal colectomy for severe acute ulcerative colitis has comparable perioperative outcomes to laparoscopic surgery.

It has been established that patients undergoing subtotal colectomy for UC benefit from a minimally invasive approach, despite the longer operating times associated with laparoscopic surgery when compared to open surgery (Andersson and Söderholm in Dig Dis 27(3):335-340, 2009; Telem et al. in Surg Endosc 24(7):1616-1620, 2010; Wu et al. in Int J Colorectal Dis 25(8):949-957, 2010). Our objective is to present our early experience with urgent robotic subtotal colectomy (RSTC) and compare them to a matched cohort of patients who underwent urgent laparoscopic subtotal colectomy (LSTC). A prospectively maintained institutional database was queried. Six RSTC patients and 13 LSTC patients were identified from 2015 to 2017. There was no difference in ASA score, body mass index, preoperative steroid use, c. difficile infection, or inflammatory markers between the groups. All patients in the robotic group and eight patients in the laparoscopic group received preoperative biologics. Neither group had intraoperative complications, open conversions, or 30-day mortality recorded. Robotic STC took 29 min longer (323.0 vs. 294.0 min, p = 0.3). There was no significant difference in blood loss between the two groups (80 ml vs. 75 ml p = 0.9). There were six postoperative complications (46%) in the laparoscopic group and 1 (20%) in the robotic group. Of these 23% (3/13) for LSTC and 0% (0/5) for RSTC were Grade III or higher. Two laparoscopic and 0 robotic patients required reoperation. The RSTC group had earlier stoma function (1.4 ± 0.8 days vs. 2 ± 1.3 days) and shorter LOS (3.4 ± 2 vs. 4.6 ± 3.2) than the LSTC group, but these did not reach statistical significance. In conclusion, urgent robotic subtotal colectomy for UC is safe and offers technical advantages.

Flavor and Nicotine Effects on E-cigarette Appeal in Young Adults: Moderation by Reason for Vaping.

Objectives: Effective regulations that reduce nicotine vaping among young adult dual (combustible and e-cigarette) users may differ depending on whether e-cigarettes are used for helping with smoking cessation. This laboratory experiment examined flavor and nicotine effects on e-cigarette product appeal among young adult dual users, stratified by reported use of e-cigarettes to quit smoking. Methods: Dual users aged 18-35 years that did (N = 31) or did not (N = 22) report vaping for the purpose of quitting smoking puffed e-cigarette solutions varied by a flavor (fruit, menthol, tobacco) and nicotine (nicotine-containing [6 mg/mL], nicotine-free) with-in-participant design. After puffing each solution, participants rated appeal. Results: In main effect analyses, non-tobacco (vs tobacco) flavors increased appeal and nicotine-containing (vs nicotine free) solutions reduced appeal similarly in dual users who did and did not vape to quit smoking. Interaction analyses found non-significant trend evidence that fruit and menthol flavors suppressed nicotine's appeal-reducing effects more powerfully in those that did not vape to quit smoking (flavor × nicotine × vape to quit smoking, ps = .05-.06). Conclusions: Non-tobacco flavors might increase e-cigarette product appeal in young adult dual users overall and disproportionately suppress nicotine's appeal-reducing effects in those that vape for purposes other than assisting with smoking cessation.

E-cigarette device power moderates the effects of non-tobacco flavors and nicotine on product appeal in young adults.

BACKGROUND: Identifying e-cigarette product characteristics that moderate the effects of non-tobacco flavors and nicotine on user appeal can inform regulations issued in tandem with e-cigarette nicotine and flavor policies aimed to protect young adult health. An e-cigarette device's electrical power affects the amount of solution aerosolized per puff, leading to more concentrated or diluted aerosol, which may alter product appeal. This laboratory experiment tested whether e-cigarette device power moderated the independent and interactive effects of non-tobacco flavors and nicotine on appeal in young adults. METHOD: In a within-subject design single-visit protocol, young adult e-cigarette users (N = 100) administered standardized doses of e-cigarette solutions varying in flavor (fruit, menthol, tobacco) and nicotine (nicotine-containing [6 mg/mL], nicotine-free). Solutions were administered via a variable-voltage tank-style device at low (7.3 W[3.3 V@1.5 Ω resistance]) and high (12.3 W[4.3 V@1.5 Ω resistance]) power settings. Participants rated each dose's appeal (0-100 scale). RESULTS: The high (vs. low) power setting attenuated the appeal-enhancing effects of menthol (vs. tobacco) flavors (Menthol × Power, estimate = -5.44, P = .03). Power did not moderate the appeal-enhancing effects of fruit flavors. High (vs. low) power amplified the appeal-reducing effects of nicotine-containing (vs. nicotine-free) solutions (Nicotine × Power, estimate = 6.69, P < .001) and augmented the extent to which fruit and menthol flavors suppressed nicotine's appeal-reducing effects (Flavor × Nicotine × Power, estimates = 9.40-14.85, Ps≤0.03). CONCLUSION: E-cigarette device power appears to moderate flavor- and nicotine-induced changes in product appeal in nuanced ways, including by augmenting the ability of non-tobacco flavors to mask nicotine's appeal-reducing effects. Regulatory restrictions on high-powered e-cigarette devices warrant consideration in efforts to protect young adult health.

Regulation of intravenous cocaine self-administration in rats selectively bred for high (HiS) and low (LoS) saccharin intake.

RATIONALE: Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (i.v.) cocaine self-administration more rapidly than their low saccharin (LoS)-consuming counterparts. The present experiment was designed to determine whether HiS and LoS rats differed in other aspects of drug abuse. OBJECTIVE: The purpose of the present experiment was to use a two-lever dose self-selection procedure to investigate the regulation/dysregulation of i.v. cocaine self-administration in female HiS and LoS rats. MATERIALS AND METHODS: HiS and LoS rats were trained to self-administer eight different doses of cocaine during daily 5-h sessions, with the cocaine doses ranging from 0.2 to 1.6 mg/kg in steps of 0.2 mg/kg. The dose size increased after a response on one lever (infusion duration lengthened by 3 s) and decreased after a response on the other lever (infusion duration shortened by 3 s), with a lower limit of 0 s and with an upper limit of 24 s (a corresponding range of 0 to 1.6 mg/kg); the animals increased or decreased their self-administered dose in nine discrete steps. RESULTS: The HiS rats showed less precise regulation of their postinfusion interval (PII) than LoS rats based on the size of the previously self-administered cocaine dose. Correlations between these variables were lower for HiS than for LoS rats during the acquisition and maintenance phases, and HiS rats had lower PIIs than LoS rats after many of the cocaine doses. The HiS rats also self-administered significantly more cocaine infusions during the maintenance phase than the LoS rats, especially at the highest dose. CONCLUSIONS: These data indicate that HiS rats are more likely to self-administer more cocaine infusions, at higher doses, and with less precise dose-time regulation than LoS rats. Thus, rats selectively bred for HiS showed less inhibitory control over their cocaine intake than LoS rats, suggesting that a genetic predisposition for saccharin preference is related to the rewarding effects of i.v. cocaine.

Acquisition of i.v. cocaine self-administration in adolescent and adult male rats selectively bred for high and low saccharin intake.

Adolescence and excessive intake of saccharin have each been previously associated with enhanced vulnerability to drug abuse. In the present study, we focused on the relationship between these two factors using male adolescent and adult rats selectively bred for high (HiS) and low (LoS) levels of saccharin intake. On postnatal day 25 (adolescents) or 150 (adults), rats were implanted with an intravenous catheter and trained to self-administer cocaine (0.4 mg/kg) using an autoshaping procedure that consisted of two 6-h sessions. In the first 6 h, rats were given non-contingent cocaine infusions at random intervals 10 times per hour, and during the second 6-h session, rats were allowed to self-administer cocaine under a fixed ratio 1 (FR 1) lever-response contingency. Acquisition was defined as a total of at least 250 infusions over 5 consecutive days, and rats were given 30 days to meet the acquisition criterion. Subsequently, saccharin phenotype scores were determined by comparing 24-h saccharin and water consumption in two-bottle tests to verify HiS/LoS status. Adolescent LoS rats had a faster rate of acquisition of cocaine self-administration than adult LoS rats; however, adolescent and adult HiS rats acquired at the same rate. Both HiS and LoS adolescents had significantly higher saccharin phenotype scores than HiS and LoS adults, respectively. Additionally, saccharin score was negatively correlated with the number of days to meet the acquisition criterion for cocaine self-administration, but this was mostly accounted for by the HiS adolescents. These results suggest that during adolescence, compared with adulthood, rats have both an increased avidity for sweets and vulnerability to initiate drug abuse.

Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake.

Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2-3 days (10-12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6 (given 2 weeks after the 5 pairs of intermittent injections). Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injection pairs 1, 5, and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS>LoS) in locomotor activity after cocaine injections 5 and 6. There was a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS>LoS and females>males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes.

Impulsivity (delay discounting) for food and cocaine in male and female rats selectively bred for high and low saccharin intake.

Previous research in rats indicates that delay discounting for food, a model of impulsivity, predicted the rate of acquisition of cocaine self-administration. In other studies, rats bred for high saccharin intake (HiS) acquired cocaine self-administration at higher rates than those with low saccharin intake (LoS), and female (F) rats acquired cocaine self-administration more rapidly than males (M). The purpose of this study was to examine a possible connection between impulsivity, saccharin intake, and sex by comparing M and F rats from the HiS and LoS selectively bred lines on measures of impulsivity; i.e., their rate of delay discounting for food or i.v. cocaine infusions. The adjusting delay procedure allowed rats access to 2 response levers, and a pellet dispenser or an i.v. drug infusion pump. In 4 groups (HiS M, HiS F, LoS M, LoS F) responses under a fixed-ratio (FR) 1 schedule on one lever resulted in one 45 mg pellet immediately, and responses on the other lever resulted in 3 or 6 pellets after a delay. Four additional groups received either a small cocaine (0.2, 0.4, or 0.8 mg/kg) infusion immediately or a delayed larger infusion (3x the amount of the small infusions). The delay to the larger reinforcer began at 6 s and increased or decreased by 1 s following responses on the delay or immediate levers, respectively. A mean adjusted delay (MAD) was calculated over 30 choice trials during each daily 3-hour session, and it was used as a quantitative measure of impulsivity. In groups maintained by food, HiS rats were more impulsive (lower MADs) than LoS rats, and LoS females were more impulsive than LoS males. There were no phenotype or sex differences in delay discounting for cocaine. Understanding the relationship between impulsivity and other predictors of drug abuse (e.g., sex, saccharin intake) is important in developing prevention and treatment strategies.

Anti-DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients.

OBJECTIVE: Treg cells oppose autoreactive responses in several autoimmune diseases, and their frequency is reduced in systemic lupus erythematosus (SLE). In murine lupus models, treatment with anti-DNA Ig-based peptides can expand the number of Treg cells in vivo. This study was undertaken to test the possibility that functional human Treg cells can be induced by exposure to anti-DNA Ig-based peptides. METHODS: Peripheral blood mononuclear cells were isolated from 36 lupus patients and 32 healthy individuals matched for ethnicity, sex, and age. Short-term culture experiments in the presence of several independent stimuli including anti-DNA Ig peptides were followed by flow cytometric analysis for identification of CD4+,CD25(high) T cells, cell sorting for in vitro suppression assays, and analysis of correlations between the expression of forkhead box P3 (FoxP3) and serologic and clinical characteristics of the SLE patients. RESULTS: The number of in vitro CD4+,CD25(high) T cells increased after culture with anti-DNA Ig peptides in the SLE patients, but not in the controls. The expanded CD4+,CD25(high) T cells required FoxP3 for cell contact-mediated suppression of proliferation and interferon-gamma production in target CD4+,CD25- T cells. The induction of FoxP3 in SLE Treg cells occurred only in seropositive patients, and was correlated with anti-DNA and IgG serum titers. CONCLUSION: These results suggest a new modality to reverse the functional deficit of Treg cells in SLE patients with positive autoimmune serology, and identify a new strategy to enhance immunoregulatory T cell activity in human SLE.

Protection against renal disease in (NZB x NZW)F(1) lupus-prone mice after somatic B cell gene vaccination with anti-DNA immunoglobulin consensus peptide.

OBJECTIVE: Ig molecules contain epitopes that can induce T cell-mediated immune responses. B cells can process and present such epitopes and activate T cells. The purpose of the present study was to test our hypothesis that T cells that recognize an Ig consensus sequence presented by B cells will modulate lupus-like disease in mice. METHODS: (NZB x NZW)F(1) (NZB/NZW) lupus mice received somatic B cell gene transfer of a DNA plasmid encoding a consensus sequence of T cell determinants of murine anti-DNA IgG or control plasmids. Treated animals were monitored for the production of antibody, the development of renal disease, and the phenotype, number, and function of T cells. RESULTS: Treatment of mice with Ig consensus plasmid induced transforming growth factor beta-producing CD8+,CD28- T cells that suppressed the antigen-specific stimulation of CD4+ T cells in a cell-contact-independent manner, reduced antibody production, retarded the development of nephritis, and improved survival. Significantly, adoptive transfer of CD8+,CD28- T cells from protected mice into hypergammaglobulinemic NZB/NZW mice effectively protected the transferred mice from the development of renal disease. CONCLUSION: Gene expression of anti-DNA Ig consensus sequence induces immunoregulatory T cells that delay the development of lupus nephritis by suppressing hypergammaglobulinemia and renal disease.