Development and characterization of a humanized mouse model of osteoarthritis.

OBJECTIVE: In light of the role of immune cells in OA pathogenesis, the development of sophisticated animal models closely mimicking the immune dysregulation during the disease development and progression could be instrumental for the preclinical evaluation of novel treatments. Among these models, immunologically humanized mice may represent a relevant system, particularly for testing immune-interacting DMOADs or cell therapies before their transfer to the clinic. Our objective, therefore, was to develop an experimental model of OA by destabilization of the medial meniscus (DMM) in humanized mice. METHOD: Irradiated 5-week-old NOD/LtSz-scid IL2Rγnull (NSG) mice were humanized by intravenous injection of CD34+ human hematopoietic stem cells. The engraftment efficiency was evaluated by flow cytometry 17 weeks after the humanization procedure. Humanized and non-humanized NSG mice underwent DMM or sham surgery and OA development was assessed 1, 6, and 12 weeks after the surgery. RESULTS: 120 days after the humanization, human T and B lymphocytes, macrophages and NK cells, were present in the blood and spleen of the humanized NSG mice. The DMM surgery induced articular cartilage and meniscal alterations associated with an increase in OA and the meniscal score. Moreover, the surgery triggered an inflammatory response that was sustained at a low grade in the DMM group. CONCLUSIONS: Our study shows for the first time the feasibility of inducing OA by DMM in humanized mice. This novel OA model could constitute a useful tool to bridge the gap between the preclinical and clinical evaluation of immune interacting DMOADs and cell-based therapies.

A multilevel analysis of condom use among adolescents in the European Union.

OBJECTIVES: This study examined which individual and national factors affect condom use among adolescents. STUDY DESIGN: Multilevel analysis. METHODS: This study reviewed the data on bullying, alcohol use and condom use provided by 18 European countries and subnational entities in the Health Behaviour in School-Aged Children survey. Another eight contextual variables were also analysed. Three multilevel logistic regression models were applied consecutively (analysing for crude geographical and school variance in condom use, adjusting for gender and adjusting all variables for one another). RESULTS: Among the 15-year-olds studied, 7.0% of the total variance in condom use was explained by school-related factors (intraschool-level correlation) and 5.8% by national/subnational factors. In the empty model, condom use was significantly associated with gender, alcohol consumption, predominant national religion and national prevalence of human immunodeficiency virus (HIV). In the full model, there was also a significant association with the Human Development Index ranking, gross domestic product, Gini coefficient and the Gender-related Development Index. CONCLUSIONS: This study suggests that while alcohol, gender, human development level, income, religion and HIV prevalence affect condom use in young Europeans, these factors do not explain all or even most of the variation. Nonetheless, since some of these factors are not traditionally associated with young people's sexual and reproductive health, these findings should enable more nuanced health policy programming.

[Factors associated with early sexual initiation in girls: French data from the international survey Health Behaviour in School-aged Children (HBSC)/WHO]. / Facteurs associés à une initiation sexuelle précoce chez les filles: données françaises de l'enquête internationale Health Behaviour in School-aged Children (HBSC)/OMS.

OBJECTIVE: Inspite of unquestionable progress, the protection of girls at first sexual intercourse is still not perfect. The main risks are well known (sexually transmitted infections [STIs], unwanted pregnancies, psychological consequences) and seem to be higher in the case of early sexual initiation. The aim of this epidemiological study is to analyse factors associated with early heterosexual intercourse (age 15 or before) among girls, considered as risk factors for pregnancies and STIs. POPULATION AND METHODS: Our data come from the 2002 international survey Health Behaviour in School-aged Children (HBSC)/WHO. The questionnaire is completed anonymously in class and measures health, health behaviours and their contexts among 11-, 13- and 15-year-old students. Only the 15 year-olds are asked about their sexual behaviour. In France, 1264 15-year-old (plus or minus six months) girls have answered the survey. RESULTS: Two hundred and twenty-four girls (17,7 %) state they have already had sexual intercourse. Among these, 88,4 % say that condoms and/or pills were used at last sexual intercourse. Multivariate analysis (n=1159) show that seven variables are significantly and independently linked to a higher frequency of early sexual intercourse: single-parent or reconstructed family, repeated drunkenness, daily smoking, cannabis experimentation, frequent evenings out, negative life appreciation and early menarche. DISCUSSION AND CONCLUSION: Identifying factors associated with early sexual initiation should help professionals to better take care of those high risk adolescent girls.

Anti-TCR Vbeta-specific DNA vaccination prolongs heart allograft survival in adult rats.

Allospecific T cells are known to play a central role in the process of allograft rejection. Recently, it has been shown that T cell function could be specifically targeted using DNA vaccination. In our model, PCR analysis of the TCR-beta chain repertoire of T cells infiltrating rejected allografts showed specific expansions of the Vbeta13 and Vbeta2 families. In this study, we tested the effect on allograft survival of DNA vaccination against a specific TCR Vbeta, in a model of heart allograft rejection in adult rats. Our results showed that anti-TCR Vbeta13 DNA vaccination lead to a significant prolongation of allograft survival compared to vaccination against other Vbeta families or untreated recipients. The prolongation of allograft survival correlated in vitro with a decrease in anti-donor reactivity of spleen cells from Vbeta13-vaccinated rats. These results show that, in a transplantation model, DNA vaccination could be used as a method to specifically manipulate a T cell response and thus prolong allograft survival.

Anti-TCR-specific DNA vaccination demonstrates a role for a CD8+ T cell clone in the induction of allograft tolerance by donor-specific blood transfusion.

Donor-specific allograft tolerance can be induced in the adult rat by pregraft donor-specific blood transfusion (DST). This tolerance appeared to be mediated by regulatory cells and to the production of the suppressive cytokine TGF-beta1. A potential immunoregulatory CD8+ clone bearing a Vbeta18-Dbeta1-Jbeta2.7 TCR gene rearrangement was previously identified in DST-treated recipients. To assess the functional role of this T cell clone in the induction of tolerance by DST, we have vaccinated DST-treated recipients with a plasmid construct encoding for the Vbeta18-Dbeta1-Jbeta2.7 TCR beta-chain. DST-induced allograft tolerance was abolished by anti-TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination in six of seven recipients, whereas vaccination with the vector alone, or with the construct encoding a TCR Vbeta13 beta-chain, had no effect. However, the transcript number of the Vbeta18-Dbeta1-Jbeta2.7 chain was unchanged in allografts from vaccinated DST-treated rats, suggesting that this clone was not depleted by vaccination, but rather was altered in its function. Moreover, TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination restored the anti-donor alloantibody production, partially restore the capacity of spleen cells from tolerized recipients to proliferate in vitro against donor cells, and decreased the inhibitory effect of TGF-beta1, seen in DST-treated recipients, in spleen cells from vaccinated DST-treated ones. This study strongly suggests that this CD8+ TCR Vbeta18-Dbeta1-Jbeta2.7 T cell clone has an effective immunoregulatory function in allograft tolerance induced by DST.

Reassessment of the role of CD8+ T cells in the induction of allograft tolerance by donor-specific blood transfusion.

Donor-specific allograft tolerance can be induced in adult rats by pregraft donor-specific blood transfusion (DST). We have previously shown that DST elicits in recipients the expansion of a donor-specific CD8+ T cell clone displaying the Vbeta18-Dbeta1-Jbeta2.7 TCR rearrangement, which rapidly infiltrates allografts after transplantation, suggesting a regulatory function for this clone in DST-induced tolerance. In this study, recipients were pretreated before grafting, using an anti-CD8 monoclonal antibody to deplete CD8+ T cells. CD8 depletion before DST and transplantation abrogated allograft tolerance, and the CD8+ T cell clone was absent from allografts. These effects were not observed when CD8 depletion was performed after DST but before transplantation. We conclude that CD8+ T cells play a role in the induction of allograft tolerance by DST.

A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance.

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in humans and animals but the immunological mechanisms of this effect remain unclear. We have analyzed the expression and the role of endogenous TGF-beta1 in a model of heart allograft tolerance, induced by pregraft DST in adult rats. We reported previously that this tolerance occurs despite a strong infiltration of leukocytes into the graft that are unable to produce both Th1- and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGF-beta1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGF-beta1. TGF-beta1-producing cells are virtually absent among early infiltrating cells in rejected grafts but are found at a later time point. The induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti-TGF-beta mAb. Moreover, overexpression of active TGF- beta1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGF-beta as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGF-beta-producing regulatory cells are also involved in allograft tolerance.