The burden of vestibular disorders among military health system (MHS) beneficiaries, fiscal years 2018-2019.

INTRODUCTION: Vestibular disorders affect an estimated 33 million adults and 3.5 million children and adolescents in the United States. Previous research relying on self-reported symptoms versus actual diagnosis has limited the ability to provide prevalence estimates for specific vestibular disorders at the population level. This study seeks to describe the burden of vestibular disorders among children and working-age adult beneficiaries in the Military Health System (MHS). MATERIALS AND METHODS: Using the MHS Data Repository (MDR), we conducted a cross-sectional study of all TRICARE Prime and Plus MHS beneficiaries aged 0 to 64 years from fiscal years (FY) 2018 to 2019. Study analyses included descriptive statistics of patient demographics and assessing the prevalence of vestibular disorders in pediatric and working-age adult beneficiaries. RESULTS: Of the 5,541,932 TRICARE Prime/Prime Plus MHS beneficiaries, 52,878 (0.95%) had a diagnosis of vestibular disorder during fiscal years 2018 to 2019, of which 1,359 were pediatric and adolescents (aged 0 to 17 years) and 51,519 were working-age adults (18 to 64 years). Vertigo was the most common diagnosis in both age-group populations (11.46 per 1,000 working-age adults; 0.52 per 1,000 children and adolescents), with benign vertigo being the most prevalent of the three diagnoses and occurring at a seven times higher rate in adults versus pediatric and adolescents. CONCLUSIONS: This study demonstrates the effectiveness of using medical claims data to estimate prevalence compared to self-reported survey data and supports prevalence estimates of vestibular disease in <1% of children overall, but indicate much higher prevalence for adolescents.

Shared injection experiences: Interpersonal involvement in injection drug practices among women.

Background: Many women who inject drugs are aware of the associated risks, however social influences play a part in their behavioral decisions. Incorporation of others in drug use behaviors may be common practice among women who use drugs. The aim of this study was to gain an in-depth understanding of women's injection drug use experiences with a focus on interpersonal involvement. Methods: Venue-based recruitment was conducted in collaboration with a harm reduction program. A group of 30 women, ages 18 and older, who reported injecting drugs within the past 30 days took part in a demographic survey and semi-structured interview to gain an understanding of their injection practices. In vivo coding and thematic analysis were conducted. Results: Three main themes that relate to incorporating others into injection drug behaviors surfaced, including: (1) injection practices described as we and not I, (2) partnered purchase and drug preparation, and (3) assisted injection. This group of women most often incorporated sexual and/or romantic partners (same and other-gender), friends, or family members into their injection drug use behaviors. Some women described a lack of ability to inject themselves and require assistance every time they use. Women also reported helping other women during drug use behaviors. Conclusions: Our primary themes indicate that a variety of relationship partners are important conceptual links in theoretical frameworks explaining drug use behaviors among women. Findings suggest same gender assistance during drug use behaviors, including injection, that may reduce harm. The interpersonal nature of injection drug use among women may indicate the expansion of treatment options designed for couples or other relationship partners, such as family, together.

ß-actin contributes to open chromatin for activation of the adipogenic pioneer factor CEBPA during transcriptional reprograming.

Adipogenesis is regulated by a cascade of signals that drive transcriptional reprogramming in adipocytes. Here, we report that nuclear actin regulates the chromatin states that establish tissue- specific expression during adipogenesis. To study the role of ß-actin in adipocyte differentiation, we conducted RNA sequencing on wild-type and ß-actin knockout mouse embryonic fibroblasts (MEFs) after reprograming to adipocytes. We found that ß-actin depletion affects induction of several adipogenic genes during transcriptional reprograming. This impaired regulation of adipogenic genes is linked to reduced expression of the pioneer factor Cebpa and is rescued by reintroducing NLS-tagged ß-actin. ATAC-Seq in knockout MEFs revealed that actin-dependent reduction of Cebpa expression correlates with decreased chromatin accessibility and loss of chromatin association of the ATPase Brg1. This, in turn, impairs CEBPB's association with its Cebpa promoter-proximal binding site during adipogenesis. We propose a role for the nuclear ß-actin pool in maintaining open chromatin for transcriptional reprogramming during adipogenic differentiation.

Existence, Distribution, and Characteristics of STD Clinics in the United States, 2017.

OBJECTIVES: Studies of sexually transmitted disease (STD) clinics have been limited by the lack of a national list for representative sampling. We sought to establish the number, type, and distribution of STD clinics and describe selected community characteristics associated with them. METHODS: We conducted a 2-phased, multilevel, online search from September 2014 through March 2015 and from May through October 2017 to identify STD clinics in all 50 US states and the District of Columbia. We obtained data on clinic name, address, contact information, and 340B funding status (which requires manufacturers to provide outpatient drugs at reduced prices). We classified clinics by type. We also obtained secondary county-level data to compare rates of chlamydia and HIV, teen births, uninsurance and unemployment, and high school graduation; ratios of primary care physician to population; health care costs; median household income; and percentage of population living in rural areas vs nonrural areas. We used t tests to examine mean differences in characteristics between counties with and without STD clinics. RESULTS: We found 4079 STD clinics and classified them into 10 types; 2530 (62.0%) clinics were affiliated with a local health department. Of 3129 counties, 1098 (35.1%) did not have an STD clinic. Twelve states had an STD clinic in every county, and 34 states had ≥1 clinic per 100 000 population. Most STD clinics were located in areas of high chlamydia morbidity and where other surrogate needs were greatest; rural areas were underserved by STD clinics. CONCLUSIONS: This list may aid in more comprehensive national studies of clinic services, STD clinic adaptation to external policy changes (eg, in public financing or patient access policy), and long-term clinic survival, with special attention to clinic coverage in rural areas.

Cardiovascular-Related Outcomes in U.S. Adults Exposed to Lead.

Cardiovascular-related clinical markers were evaluated in this cross-sectional study of United States adults (aged ≥ 20) exposed to lead via the National Health and Nutrition Examination Survey 2007-2008 and the 2009-2010 datasets. In four quartiles of exposure-0-2 µg/dL, 2-5 µg/dL, 5-10 µg/dL, and 10 µg/dL and over, clinical and anthropometric markers were evaluated-to examine how the markers manifested in the quartiles. Associations were determined via linear regression. Finally, clinical makers, and how they manifested between exposed and less-exposed occupations, were explored in addition to how duration of exposure altered these clinical markers. In regression analysis, Diastolic Blood Pressure (DBP) and high-density lipoprotein (HDL) cholesterol, were significantly associated with blood lead level (BLL). In the occupational analysis, Systolic Blood Pressure (SBP), DBP, C-reactive protein (CRP), triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, showed differences between populations in the exposed and less-exposed occupations. Regarding Agriculture, Forestry & Fishing, the duration of exposure altered SBP, CRP, and LDL cholesterol. With mining, the duration of exposure altered SBP, DBP, triglycerides, and HDL cholesterol, whereas in construction, the duration in occupation altered SBP, triglycerides, and CRP. In conclusion, lead exposure has a profound effect on the cardiovascular system, with potentially adverse outcomes existing at all exposure levels.

A systematic review comparing single-incision versus multi-incision laparoscopic surgery for inguinal hernia repair with mesh.

OBJECTIVE: The objective of this article is to evaluate whether the surgical outcomes differ between single incision laparoscopic surgery (SILS) versus multi-incision laparoscopic surgery (MILS) for the repair of inguinal hernia. METHODS: A systematic review of the literature on published studies reporting the surgical outcomes following SILS versus MILS for inguinal hernia repair was undertaken using the principles of meta-analysis. RESULTS: Fifteen comparative studies on 1651 patients evaluating the surgical outcomes in patients undergoing SILS versus MILS for inguinal hernia repair were systematically analysed. The post-operative recovery time was significantly quicker [odds ratio, -0.35 (CI, -0.57 - 0.14), p = 0.001] following SILS compared to MILS procedure. However, the statistical equivalence was seen in outcomes of length of hospital stay, operative time both for unilateral and bilateral hernias, post-operative pain score, one-week pain score, hernia recurrence [odds ratio, 1.24 (CI, 0.47-3.23), p = 0.66], conversion [odds ratio, 1.07 (CI, 0.37-3.12), p = 0.90], and post-operative complications [odds ratio, 0.95 (CI, 0.66-1.36, p = 0.78] between two approaches. The sub-group analysis of four included randomized, controlled trials showed similarities between outcomes following SILS and MILS except slightly higher postoperative pain score in MILS group. CONCLUSIONS: Both SILS and MILS approaches of inguinal hernia repair are feasible, safe and can be offered to patients depending upon the availability of expertise and resources.

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

State Size and Government Level Matter Most: A Structural Equation Model of Local Health Department Policy Behaviors.

OBJECTIVE: To explore relationships between local health department policy behaviors, levels of government activity, policy focus areas, and selected health department characteristics. DESIGN: Cross-sectional analysis of secondary data from the 2013 National Association of County & City Health Officials (NACCHO) Profile Survey. SETTING: Local health departments throughout the United States. PARTICIPANTS: A total of 2000 local health departments responding to the 2013 Profile Survey of Local Health Departments. Survey data were gathered by the NACCHO. METHODS: Secondary analysis of reported policy behaviors for the 2013 NACCHO Profile Survey. A structural equation model tested effects on and between state population size, rurality, census region and policy focus, and the latent variables of policy behavior formed from a confirmatory factor analysis. MAIN OUTCOME MEASURES: Policy behaviors, levels of government activity (local, state, and federal), policy focus areas, and selected local health department characteristics. RESULTS: The majority (85.1%) of health departments reported at least one of the possible policy behaviors. State population size increased the probability of local policy behavior, and local behavior increased the probability of state policy behavior. State size increased the likelihood of federal policy behavior and the focus on tobacco, emergency preparedness, and obesity/chronic disease. However, the more rural a state was, the more likely policy behavior was at the state and federal levels and not at local levels. Specific policy behaviors mattered less than the level of government activity. CONCLUSIONS: Size of state and rurality of health departments influence the government level of policy behavior.

Cervical cancer screening in a sexually transmitted disease clinic: screening adoption experiences from a midwestern clinic.

OBJECTIVES: We examined whether a sexually transmitted disease (STD) clinic could reach women who had not received a Papanicolau (Pap) test in the past 3 years. We also explored staff attitudes and implementation of cervical cancer screening. METHODS: Women (n = 123) aged 30 to 50 years were offered cervical cancer screening in an Indiana STD clinic. We measured effectiveness by the patients' self-reported last Pap test. We explored adoption of screening through focus groups with 34 staff members by documenting their attitudes about cervical cancer screening and screening strategy adaptation. We also documented recruitment and screening implementation. RESULTS: Almost half (47.9%) of participants reported a last Pap test 3 or more years previously; 30% had reported a last Pap more than 5 years ago, and 11.4% had a high-risk test outcome that required referral to colposcopy. Staff supported screening because of mission alignment and perceived patient benefit. Screening adaptations included eligibility, results provision, and follow-up. CONCLUSIONS: Cervical cancer screening was possible and potentially beneficial in STD clinics. Future effectiveness-implementation studies should expand to include all female patients, and should examine the degree to which adaptation of selected adoption frameworks is feasible.

T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells.

BACKGROUND: Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4(+) T cells and increased levels of thymus and activation-regulated chemokine (TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH 2 responses via CCL17 production. OBJECTIVES: To elucidate the mechanisms involved in allergen-specific T cell-induced LAR and recruitment of CD4(+) T cells by examining the effects of T cell-derived factors on the induction of TSLP in primary bronchial epithelial cells (PBEC). METHODS: PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (dsRNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (moDC). RESULTS: Both dsRNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from moDC in a manner related to clinical asthmatic status. IL-1ß, IL-6, and CXCL8, rather than TH 2 cytokines (IL-4/5/13), appeared to be the principle mediators of allergen-specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFκB pathways. CONCLUSION AND CLINICAL RELEVANCE: Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell-airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression (T cell-derived factors) may be equally relevant in the treatment of allergic inflammation.

Deleterious effect of CTLA4-Ig on a Treg-dependent transplant model.

Blockade of the B7:CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, results from the belatacept phase III clinical trial demonstrated a higher rejection rate when compared to cyclosporine, raising concern about potential deleterious effects of this agent. In this study, we investigated the consequences of B7:CD28 blockade by hCTLA4Ig on regulator T cell (Treg) generation in different major histocompatibility complex (MHC) mismatch transplant models. Administration of hCTLA4Ig significantly decreased the amount of Tregs in B6 WT animals and this effect was predominant in thymus-induced Tregs (Helios(+) ). Although hCTLA4Ig prevented rejection in a fully allogeneic mismatch model, it accelerated rejection in a MHC class-II mismatch model (MST = 26, p < 0.0001), in which long-term allograft survival is dependent on Tregs. This accelerated rejection was associated with a marked reduction in thymus-induced Tregs and led to a higher effector/regulatory T-cell ratio in secondary lymphoid organs and in the allograft. This study confirms the importance of the B7:CD28 pathway in Treg homeostasis in an in vivo transplant model and suggests that hCTLA4Ig therapy may be deleterious in circumstances where engraftment is dependent on Tregs.

Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance.

The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.

Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts.

The PD1:PDL1 pathway is an essential negative costimulatory pathway that plays a key role in regulating the alloimune response. PDL1 is expressed not only on antigen-presenting cells (APCs) but also cardiac endothelium. In this study, we investigated the importance of PDL1 expression on donor cardiac allograft in acquired transplantation tolerance in a fully MHC-mismatched model. We generated PDL1 chimeric mice on B6 background that expressed PDL1 on either hematopoietic cells or nonhematopoietic cells of the heart. Sham animals were used as controls. These hearts were then transplanted into BALB/c recipients and treated with CTLA4-Ig to induce tolerance. Cardiac endothelium showed significant expression of PDL1, which was upregulated upon transplantation. While the absence of PDL1 on hematopoietic cells of the heart resulted in delayed rejection and prevented long-term tolerance in most but not all recipients, we observed an accelerated and early graft rejection of all donor allografts that lacked PDL1 on the endothelium. Moreover, PDL1-deficient endothelium hearts had significant higher frequency of IFN-γ-producing alloreactive cells as well as higher frequency of CD8(+) effector T cells. These findings demonstrate that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.

Use of staple-line reinforcement in laparoscopic gastric bypass surgery: a meta-analysis.

OBJECTIVE: This article was designed to systematically analyze the prospective, randomized, controlled trials on the effectiveness of staple-line reinforcement (SLR) in patients undergoing laparoscopic gastric bypass (LGBP) surgery. METHODS: Trials on the effectiveness of SLR in patients undergoing LGBP surgery were selected electronic data bases and analyzed to generate summative data by using the principles of meta-analysis on statistical software package RevMan 5.0.2 provided by Cochrane Collaboration. Combined outcome of the binary variables was expressed as odds ratio (OR) and continuous variables were expressed as standardized mean difference (SMD). RESULTS: Three randomized, controlled trails on 180 patients qualified for inclusion. There were 91 patients in SLR group and 89 patients in non-staple-line reinforcement (NSLR) group. There was no heterogeneity among trials. In the fixed-effects model, SLR is equivalent to NSLR in terms of controlling bleeding (odds ratio (OR), 0.32; 95% confidence interval (CI), 0.03, 3.18; z = 0.98; P < 0.33) from the staple-line and total number of staples used (standardized mean difference (SMD), -21.01; 95% CI, -56.46, 14.44; z = 1.16; P < 0.25) for anastomosis. SLR significantly reduces operative time (SMD, -0.76; 95% CI, -1.36, -0.16; z = 2.47; P < 0.01), perioperative complications (OR, 0.19; 95% CI, 0.05, 0.68; z = 2.55; P < 0.01), anastomotic leak (OR, 0.1; 95% CI, 0.01, 0.78; z = 2.2; P < 0.03), and hemostatic clips (SMD, -21.01; 95% CI, -56.46, 14.44; z = 1.16; P < 0.25) usage. CONCLUSIONS: SLR seems to reduce the operative time in LGBP. In addition, SLR is associated with fewer postoperative complications, reduced incidence of anastomotic leak, and reduced requirement of hemostatic clips to control hemorrhage at the staple line. However, SLR does not have any superiority in terms of controlling staple-line bleeding and does not influence the number of staples used in LGBP.

Donor antioxidant strategy prolongs cardiac allograft survival by attenuating tissue dendritic cell immunogenicity(†).

Ischemic reperfusion injury (IRI) enhances allograft immunogenicity, worsens transplantation outcome, and is the primary cause of activation of the recipient innate immune response, resulting in subsequent amplification of the alloimmune adaptive response. Here, we aimed at demonstrating that the link between innate injury and alloimmunity occurs predominantly through activation of allograft-derived dendritic cells (ADDC). Perfusion of MCI-186, a free radical scavenger, into donor cardiac allografts prior to transplantation resulted in prolongation of complete MHC-mismatched allograft survival in the absence of immunosuppression (MST of 8 vs. 26 days). This prolongation was associated with a reduction in trafficking of ADDC to recipient lymphoid tissue as well as a reduction in T cell priming. Depleting ADDC with diphtheria toxin (using DTR-GFP-DC mice as donors) 24 h prior to transplant resulted in abrogation of the prolongation observed with MCI-186 treatment, demonstrating that the beneficial effect of MCI-186 is mediated by ADDC. This donor-specific anti-ischemic regimen was also shown to reduce chronic rejection, which represents the primary obstacle to long-term allograft acceptance. These data for the first time establish a basis for donor anti-ischemic strategies, which in the ever-expanding marginal donor pools, can be instituted to promote engraftment.

Overweight among low-income Texas preschoolers aged 2 to 4 years.

OBJECTIVE: Determine child/maternal factors associated with overweight among 2- to 4-year-olds enrolled in the Texas Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). DESIGN: Matched child and maternal data collected by self-report of the mother during WIC certification. These data were extracted from existing statewide WIC databases and merged. SETTING: Texas WIC children aged 2 to 4 years in April 2006. PARTICIPANTS: Final sample was 22,837 mother-child dyads. MAIN OUTCOME MEASURE: Dependent variable--child overweight; independent variables: Child-related--gender, age, race/ethnicity, Medicaid status, living area, and dental problems; Maternal-related--certification status, age, times certified, overweight, high maternal weight gain, and gestational diabetes. ANALYSIS: Bivariate relationships at P < .05 were included in the logistic regression. RESULTS: Living in a nonborder urban area associated with greater odds of overweight compared to living in a border area. Mother's overweight, high gestational weight gain, and gestational diabetes associated with greater odds of child overweight. CONCLUSIONS AND IMPLICATIONS: Several child- and maternal-related factors were found to be associated with overweight in Texas WIC preschoolers. Health interventions should target 4-year-old Hispanic children living in nonborder urban areas and mothers who are overweight, have high gestational weight gain, or have gestational diabetes.

Teen pregnancy in Texas: 2005 to 2015.

OBJECTIVES: Texas birth records and population projections were used to simulate pregnancy rates among women ages 15-19 years from 2005 to 2015. METHODS: Monte Carlo simulation based on historical rates of natural increase, contraceptive failure and sexual experience among racial/ethnic groups of teenaged women was used for numerical projections. These projections were used in a systems dynamics model which posits teen pregnancy risk as a stochastic process of contraceptive failure and sexual activity. The PRI was constructed as a logistic function of sexual experience, the weighted average contraceptive failure rates and time-varying probabilities of natural increase among racial/ethnic sub-groups of adolescent women. RESULTS: From 2005 to 2015, the number of adolescent, Hispanic females in Texas is expected to increase by 45%. During this same period, the expected pregnancy risk for 15 to 19 year old females is expected to increase to 13% or 127 per 1,000 women. This increase is due largely to the rise in the pregnancy risk among the growing population of Hispanic adolescents. CONCLUSIONS: Changing population characteristics in Texas and differences in sexual activity and contraceptive failure among racial/ethnic groups indicate that teenage pregnancy will not continue to decline in the coming decade. The adolescents most at risk for pregnancy are expected to increase significantly. Pregnancy prevention programs need to be intensified and adapted to the changing Texas social climate in order to preempt dramatic increases in teenage pregnancy.

Paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched cardiac transplant model.

Blockade of the B7: CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, this pathway has also been demonstrated to be important for the generation and maintenance of regulatory T cells. In this study, we investigated the role of the B7: CD28 pathway in the 'bm12 into B6' MHC class II-mismatched vascularized cardiac transplant model of chronic rejection. Allograft rejection was remarkably accelerated in B6 background B7DKO and CD28KO recipients compared with B6 wild-type (WT) recipients. Allograft rejection was associated with a significantly enhanced Th1/Th2 alloreactivity and marked reduction in the ratio of regulatory T cells to CD4(+) effector/memory cells. We noted that administration of anti-B7-1 and anti-B7-2 mAb prior to transplantation also accelerated allograft rejection. Furthermore, depleting CD25(+) cells in B6 WT recipients of bm12 hearts prior to transplant also precipitated rejection at a similar rate. Neither B7/CD28 deficiency nor CD25 depletion affected graft survival in single MHC class I-mismatched (bm1 into B6) recipients. This study highlights the paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched model, in which the B7: CD28 pathway is demonstrated to be important in preventing rejection through the generation and maintenance of Tregs.

Regulatory T cells in transplantation: what we know and what we do not know.

Current immunosuppressive regimens suppress alloimmunity by nonspecifically targeting T-cell proliferation, differentiation, and activation. In doing so, they have been effective in dramatically reducing rates of acute rejection and improving short-term allograft survival. However, this is often at the expense of overimmunosuppression. Furthermore, chronic rejection remains a significant problem. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) act to counterbalance effector mechanisms in immune homeostasis. Their function has been shown to be critical in autoimmune disease, transplantation, and allergy and inflammation. In this article, we will explore the current knowledge of Treg immunobiology in experimental models, as well as in human organ transplantation. The impact of current immunosuppressive agents on Tregs will be reviewed, and future promising targets for Treg-based therapies will be explored.