Arabidopsis petiole torsions induced by lateral light or externally supplied auxin require microtubule-associated TORTIFOLIA1/SPIRAL2.

Although rather inconspicuous, movements are an important adaptive trait of plants. Consequently, light- or gravity-induced movements leading to organ bending have been studied intensively. In the field, however, plant movements often result in organ twisting rather than bending. This study investigates the mechanism of light- or gravity-induced twisting movements, coined "helical tropisms." Because certain Arabidopsis cell expansion mutants show organ twisting under standard growth conditions, we here investigated how the right-handed helical growth mutant tortifolia1/spiral2 (tor1) responds when stimulated to perform helical tropisms. When leaves were illuminated from the left, tor1 was capable of producing left-handed petiole torsions, but these occurred at a reduced rate. When light was applied from right, tor1 plants rotated their petioles much faster than the wild-type. Applying auxin to the lateral-distal side of wild-type petioles produced petiole torsions in which the auxinated flank was consistently turned upwards. This kind of movement was not observed in tor1 mutants when auxinated to produce left-handed movements. Investigating auxin transport in twisting petioles based on the DR5-marker suggested that auxin flow was apical-basal rather than helical. While cortical microtubules of excised wild-type petioles oriented transversely when stimulated with auxin, those of tor1 were largely incapable of reorientation. Together, our results show that tor1 is a tropism mutant and suggest a mechanism in which auxin and microtubules both contribute to helical tropisms.

Complex regional pain syndrome: a comprehensive and critical review.

Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence-based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unnecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is.

Serial plasma vasopressin concentration in healthy and hospitalised neonatal foals.

REASONS FOR PERFORMING STUDY: Vasopressin dysregulation occurs in critically ill human patients and in neonatal foals. Limited data about serial plasma vasopressin dynamics exist in sick neonatal foals. OBJECTIVES: To evaluate serial plasma arginine vasopressin (AVP) concentrations in sick neonatal foals. STUDY DESIGN: Prospective, longitudinal clinical study. METHODS: Plasma samples were collected from 7 healthy and 26 sick foals before and after initial fluid resuscitation and 12, 24, 36, 48 and 96 h after presentation. Foals with a modified sepsis score ≥ 11 were considered septic. RESULTS: Admission AVP was increased in septic foals compared to healthy and to sick, nonseptic foals. There were no significant differences between groups on subsequent days. Nonsurvivors had higher AVP concentrations than survivors. CONCLUSIONS: Plasma AVP concentrations are higher in septic foals on admission than in healthy and sick nonseptic foals. Higher early plasma AVP concentrations are associated with increased mortality.

Sequential L-lactate concentration in hospitalised equine neonates: A prospective multicentre study.

REASONS FOR PERFORMING STUDY: Evaluation of serial blood lactate concentrations [LAC] are of prognostic value for morbidity and mortality in critically ill human patients and neonatal foals, but have not been prospectively evaluated in a large multicentre study of critically ill neonatal foals. OBJECTIVES: To prospectively evaluate the prognostic value of sequential [LAC] analysis in critically ill neonatal foals with risk of mortality. STUDY DESIGN: Prospective, observational study. METHODS: Thirteen university and private equine referral hospitals enrolled 643 foals over the 2008 foaling season and [LAC] was measured at admission ([LAC]ADMIT ) and 24 ([LAC]24 ), 48 ([LAC]48 ), 72 ([LAC]72 ), 96 ([LAC]96 ) and 120 h ([LAC]120 ) after admission. [LAC] changes over time ([LAC]Δ) were calculated between sampling points. RESULTS: Nonsurvivors had significantly greater [LAC]ADMIT , [LAC]24 and [LAC]48 compared with surviving foals (P<0.001). In nonsurviving foals [LAC]Δ did not decrease over time while survivors showed significant positive [LAC]Δ between [LAC]ADM -24 and all other time periods (P<0.001). Logistic regression analysis showed that the odds of survival decreased for each 1 mmol/l [LAC] increase at all time points for all critically ill foals, independent of major final diagnoses as potential confounders. Septic foals had significantly greater [LAC] at all time points compared with nonseptic foals (P<0.001) and [LAC]Δ in septic foals was significantly more positive (suggesting better clearance of lactate from the blood) only at [LAC]ADM -24 and [LAC]72-96 (P<0.01), while in nonseptic foals [LAC]Δ was significantly positive between [LAC]ADM -24 compared with all other time periods (P<0.001). CONCLUSIONS: Blood lactate concentration is a strong, independent biomarker used to predict mortality in critically ill foals. Lactate metabolism is impaired in nonsurviving and septic foals and [LAC]Δ can be utilised to identify patients at high risk for mortality.

Association of admission L-lactate concentration in hospitalised equine neonates with presenting complaint, periparturient events, clinical diagnosis and outcome: a prospective multicentre study.

REASONS FOR PERFORMING THE STUDY: Admission L-lactate concentration is a useful and commonly measured biomarker not previously prospectively evaluated in a large multicentre study of critically ill neonatal foals. OBJECTIVES: To evaluate overall outcome and the association of survival and L-lactate concentration at admission ([LAC]ADMIT) by periparturient history, presenting complaint and clinicians' major diagnosis for ill neonatal foals. METHODS: Thirteen university and private equine referral hospitals enrolled 643 foals over the 2008 foaling season. Case details, historical, clinical and clinicopathological data were entered into standardised spreadsheets then unified for analysis. RESULTS: Overall survival was 79% (505/643). Risk of nonsurvival increased with each 1 mmol/l increase in [LAC]ADMIT (odds ratio 1.14, P < 0.001). Mean arterial pressure had a small (r2 = 19.1) but significant (P < 0.001) association with [LAC]ADMIT. Foals experiencing known dystocia or premature placental separation had increased [LAC]ADMIT (P < 0.001). Single umbilical problems (excluding uroperitoneum), meconium impaction only and failure of passive transfer of immunity only had 100% survival. Six clinicians' major diagnoses had increased odds of nonsurvival for each 1 mmol/l increase in [LAC]ADMIT: 'sepsis'; 'unspecified enterocolitis'; 'unspecified colic'; 'unspecified trauma'; 'immune related (not failure of passive transfer of immunity)' and 'respiratory only'. CONCLUSIONS AND POTENTIAL RELEVANCE: Survival of critically ill foals is good but varies with peripartum history, presenting complaint and clinicians' major diagnosis. L-lactate concentration at admission proves its utility as a valuable prognostic biomarker in neonatal foals and its utility appears to vary with peripartum history and clinicians' major diagnosis.

Increased accumulation and stability of rotavirus VP6 protein in tobacco chloroplasts following changes to the 5' untranslated region and the 5' end of the coding region.

Rotavirus is the main cause of gastroenteritis in children worldwide, and the World Health Organisation has recommended that a rotavirus vaccine should be included in all infant immunization programmes. VP6 is the most immunogenic rotavirus subunit and is a potential target for an oral subunit vaccine. VP6 accumulated at up to 3% of total soluble protein in the young leaves of transplastomic tobacco plants, but the protein was unstable and was lost as the leaves aged. The aim of this study was to alter the 5'-untranslated region (5'-UTR) and the 5' end of the coding region of VP6 cDNA in an attempt to increase the expression and stability of VP6 protein in tobacco chloroplasts. The inclusion of the 5'-UTR from gene 10 of bacteriophage T7 (T7g10) and the addition of 15 nucleotides, encoding five additional amino acid residues, at the 5' end of the coding region increased the expression to >15% of total leaf protein and stabilized the protein in ageing leaves. Plants containing VP6 expression constructs with the rbcL 5'-UTR and with the native VP6 5' end of the coding region produced VP6 protein at only 1.9% of total leaf protein. Both the T7g10 5'-UTR and the additional 15 nucleotides increased transcript accumulation and translational efficiency compared with VP6 constructs containing the rbcL 5'-UTR. The VP6 protein produced from all gene constructs appeared to be susceptible to proteolytic processing at its N-terminal region. However, in all transplastomic lines, VP6 proteins assembled into the trimeric form found in the rotavirus capsid.

High-level expression of human immunodeficiency virus antigens from the tobacco and tomato plastid genomes.

Transgene expression from the plant's plastid genome represents a promising strategy in molecular farming because of the plastid's potential to accumulate foreign proteins to high levels and the increased biosafety provided by the maternal mode of organelle inheritance. In this article, we explore the potential of transplastomic plants to produce human immunodeficiency virus (HIV) antigens as potential components of an acquired immunodeficiency syndrome (AIDS) vaccine. It is shown that the HIV antigens p24 (the major target of T-cell-mediated immune responses in HIV-positive individuals) and Nef can be expressed to high levels in plastids of tobacco, a non-food crop, and tomato, a food crop with an edible fruit. Optimized p24-Nef fusion gene cassettes trigger antigen protein accumulation to up to approximately 40% of the plant's total protein, demonstrating the great potential of transgenic plastids to produce AIDS vaccine components at low cost and high yield.

[Postoperative pain therapy with tilidin and tilidin retard as an oral patient-controlled analgesia after uncomplicated myocardial revascularization]. / Die postoperative Schmerztherapie mit Valoron-N-Lösung und Valoron-N-retard. Tabletten als orales Patienten-kontrolliertes Analgesieverfahren nach herzchirurgischen Routine-Bypassoperationen.

OBJECTIVE: The purpose of this study was to evaluate whether or not the combination of tilidin and tilidin retard as oral patient-controlled analgesia provide a suitable pain management in patients after uncomplicated myocardial revascularization. METHODS: We conducted a randomised phase IV study to evaluate the effectiveness of postoperative analgesia with tilidin and tilidin retard. Patients with a baseline tilidin retard and tilidin liquid demand medication (group B, 42 patients) were compared with a base line paracetamol and tramadol-HCl liquid demand medication (group A, 44 patients). All patients received the first dose of study medication at the second postoperative day after evaluation of the individual pain score using NRS (numeric rating scale). RESULTS: Pain relief in group B was significantly better only at the second postoperative day (NRS 1,8 compared to 3,3 in group A), associated with tolerable side effects and comfortable handling. CONCLUSION: The combination of sustained release with immediate release drugs as a patient controlled analgesia provides suitable and comfortable analgesia after myocardial bypass surgery.

Xenopus cadherin-11 restrains cranial neural crest migration and influences neural crest specification.

Cranial neural crest (CNC) cells migrate extensively, typically in a pattern of cell streams. In Xenopus, these cells express the adhesion molecule Xcadherin-11 (Xcad-11) as they begin to emigrate from the neural fold. In order to study the function of this molecule, we have overexpressed wild-type Xcad-11 as well as Xcad-11 mutants with cytoplasmic (deltacXcad-11) or extracellular (deltaeXcad-11) deletions. Green fluorescent protein (GFP) was used to mark injected cells. We then transplanted parts of the fluorescent CNC at the premigratory stage into non-injected host embryos. This altered not only migration, but also the expression of neural crest markers. Migration of transplanted cranial neural crest cells was blocked when full-length Xcad-11 or its mutant lacking the beta-catenin-binding site (deltacXcad-11) was overexpressed. In addition, the expression of neural crest markers (AP-2, Snail and twist) diminished within the first four hours after grafting, and disappeared completely after 18 hours. Instead, these grafts expressed neural markers (2G9, nrp-I and N-Tubulin). Beta-catenin co-expression, heterotopic transplantation of CNC cells into the pharyngeal pouch area or both in combination failed to prevent neural differentiation of the grafts. By contrast, deltaeXcad-11 overexpression resulted in premature emigration of cells from the transplants. The AP-2 and Snail patterns remained unaffected in these migrating grafts, while twist expression was strongly reduced. Co-expression of deltaeXcad-11 and beta-catenin was able to rescue the loss of twist expression, indicating that Wnt/beta-catenin signalling is required to maintain twist expression during migration. These results show that migration is a prerequisite for neural crest differentiation. Endogenous Xcad-11 delays CNC migration. Xcad-11 expression must, however, be balanced, as overexpression prevents migration and leads to neural marker expression. Although Wnt/beta-catenin signalling is required to sustain twist expression during migration, it is not sufficient to block neural differentiation in non-migrating grafts.

Integrin- and cadherin-mediated induction of the matrix metalloprotease matrilysin in cocultures of malignant oral squamous cell carcinoma cells and dermal fibroblasts.

Matrilysin is a matrix metalloprotease (MMP) overexpressed in a number of cancers including skin, head and neck squamous cell carcinomas, and prostate and colon adenocarcinomas. Matrilysin has been shown to play a role in the degradation of the basement membrane that separates epithelium from stroma allowing tumor cells to intravasate into the bloodstream and metastasize. Here, we show that an oral squamous cell carcinoma cell line (SCC-25) expresses low levels of promatrilysin when cultured alone. However, when SCC-25 cells are cocultured with human foreskin fibroblasts (HFF), there is a 40-fold induction of promatrilysin expression. We tested whether this induction of promatrilysin expression was due to the release of paracrine factors, cell-cell interactions, or cell-matrix interactions. Our results indicate induced promatrilysin expression is the result of both cell-cell and cell-matrix interactions. We demonstrate that beta1 integrins as well as cadherins, specifically N-cadherin and E-cadherin, are involved in the induction of promatrilysin expression. Our results are of general interest in relation to the regulation of MMP expression through cell surface receptor regulation. Further investigation may lead to the identification of novel targets for suppression of invasion and metastasis in oral tumors.

Calorie restriction in obesity: prevention of kidney disease in rodents.

The incidence of end-stage renal disease (ESRD) has risen considerably in the past two decades. This trend is partly due to the alarming rise in the incidence of type 2 diabetes over the same period, which in turn might be linked to the staggering increase in overweight and obesity. If these trends continue, ESRD can be expected not only to cause suffering of ever growing numbers of patients, but also to become an increasing financial as well as logistical burden on the health care system. Therefore, it is imperative not only to gain a better understanding of the molecular, cellular and metabolic mechanisms involved in renal pathology, but also to uncover treatment modalities, including lifestyle changes, that can help prevent and/or slow the progression of kidney pathogenesis. Insights into both of these aspects are provided by animal models of obesity and diabetes. It has long been known that food restriction, more so than restriction of any particular dietary component, can greatly enhance longevity in laboratory rodents. These findings are being extended into a variety of other mammals, including nonhuman primates. These studies have indicated that caloric restriction in nonobese laboratory animals does not primarily affect specific disease processes but rather nonspecifically slows the aging process. In contrast, a growing body of evidence suggests that in genetically obese animals, food restriction can prevent or greatly delay the onset of specific degenerative lesions, in particular glomerulonephritis associated with obesity and diabetes.

Genetic and familial considerations of primary biliary cirrhosis.

The genetic basis of human autoimmune diseases is receiving increasing attention. Primary biliary cirrhosis (PBC) is a model autoimmune disease reflective of other organ-specific autoimmune pathology. PBC is an enigmatic autoimmune disease that predominantly affects women and leads to destruction of intrahepatic bile ducts. The serological hallmark of this disease is characterized by antimitochondrial antibodies that specifically react with the E2 components of 2-oxodehydrogenase enzymes, including PDC-E2. There are no clear major histocompatibility complex associations with the development of PBC, despite the observation that first-degree relations of index patients with PBC have a 4-6% prevalence of development of PBC. This risk factor is comparable or higher than any other human autoimmune disease and suggests that a genome-wide approach towards dissection of genetic associations would lead to valuable new insights. In this review, we place these concepts in perspective and highlight in particular the genetic associations in PBC and the importance of studying siblings with PBC who are concordant for disease.

Shosaiko-to and other Kampo (Japanese herbal) medicines: a review of their immunomodulatory activities.

The use of alternative medicine, including consumption of herbal products and dietary supplements, has been increasing substantially both in the United States and in Western Europe. One area that is garnering increased attention is the use of Oriental Medicine including Kampo, or Japanese herbal medicine. Herein, we review representative examples of research available on the most common use of Kampo medicinals, namely to improve the immune response. We also provide an extensive background on the history of Kampo. There are more than 210 different Kampo formulae used in Japan and most uses of Kampo are to modulate the immune response, i.e. to improve immunity. We have extracted data on seven common Kampo medicinals, and the data are reviewed with respect to in vitro and in vivo activities for both humans and experimental animals; the ingredients as well as the problems with classification of these materials are presented. Research suggests that Kampo herbals are biologically active and may have therapeutic potential. While it is believed that Kampo medicines have few side effects, there is a paucity of data on their toxicity as well as a relative lack of knowledge of the bioactive constituents and potential drug interactions of these agents.

Inflammation and Native American medicine: the role of botanicals.

There is a growing interest in medicinal botanicals as part of complementary medicine in the United States. In particular, both physicians and consumers are becoming aware of the use of herbals by Native American societies; many botanicals sold today as dietary supplements in the United States were used by Native Americans for similar purposes. Yet, these supplements represent only a small number of the >2500 different plant species from vascular taxa, and >2800 species from all taxa, known to have been prized for their medicinal properties by the indigenous inhabitants of the North American continent. We review some of the studies of the immunomodulatory activities of botanicals used by native peoples of North America, the bioactive constituents responsible for those activities, and the mechanisms by which these constituents might modulate the immune system. We focus particularly on 3 species of purple coneflower (ECHINACEA:) because of the widespread use of purple coneflower in the United States to boost immunity and prevent upper respiratory infections. Seven of the 10 most common botanicals sold in the United States were used extensively by Native Americans. However, there are very few data to support such use and even less information about drug toxicity or interactions.

Phenotypic and functional considerations in the evaluation of immunity in nutritionally compromised hosts.

It is well established that proper nutrition is critical to the development of an effective immune system and to enhance the natural immunosurveillance and its effector mechanisms. This enhancement could be mediated either by increasing the frequency and absolute numbers of effector cells or by up-regulation of the cellular mechanisms by which these effector cells carry out their functions. Even in the Western world, large sectors of society often remain undernourished and show suboptimal immune responses, but the relationship between nutrition and immunity is best seen in developing and underdeveloped countries. Although there are many large-scale field studies that investigate the issue of nutrition and immunity, there are relatively few data that go beyond descriptive measurements and directly address how well the immune system functions. This review summarizes interactions between nutrition and immunity and focuses on practical aspects for evaluation of the immune function in the field.

The pathogenesis of autoimmunity in New Zealand mice.

OBJECTIVE: New Zealand mice were the first spontaneous animal model of human systemic lupus erythematosus (SLE). Since their initial discovery in 1959, studies of these mice have provided insights into the immunopathogenesis and genetics of lupus and have had a substantial impact on our understanding of autoimmunity. METHODS: We extensively reviewed published data for the past 40 years, including work in cellular immunology and molecular biology, to provide new information on the role of lymphoid subpopulations, cytokines, costimulatory molecules, apoptosis, and genetic susceptibility in the natural history of immunopathology in murine lupus. RESULTS: Genetic factors constitute the most important contribution to autoimmunity in New Zealand mice, and specific major susceptibility loci have been described. In addition, there is evidence for a pluripotent stem cell defect, which has implications for developmental and functional defects of T and B cells. The end result of these defects is a breakdown of self-tolerance and production of autoantibodies. Further studies will undoubtedly shape our understanding of this murine model and provide the basis for novel diagnostic and therapeutic approaches in humans. CONCLUSIONS: The advent of molecular biology, including the use of monoclonal antibody therapy in New Zealand mice, has been instrumental in our understanding of the loss of self-tolerance in SLE. Finally, identification of genetic susceptibility loci in the murine system has also led to important comparable studies in humans with SLE. RELEVANCE: The observations in New Zealand mice are of particular importance to systemic lupus erythematosus (SLE).

How to outfox mother nature--autoimmunity: moving from shadows to sunshine.

The morbidity and disability associated with autoimmune diseases represent a significant health problem. One in 31 people have one form or another of an autoimmune disease. Despite the avalanche of molecular data, immunogenetic definitions and improvements in serologic diagnosis, we are still far from discovering the etiologies of these diseases. For some autoimmune diseases, there may be a very long latency period between disease onset and clinical presentation. Existing therapies tend to be only partially successful and often accompanied by a variety of serious side effects. However, even in the absence of a complete understanding of the underlying genetic, environmental and coincidental factors that confer susceptibility to autoimmune diseases, we believe that it is possible to devise successful therapies by interfering with one or more of the pathways of destruction characteristic of a specific autoimmune disease. We have prepared a futuristic look at the treatment of autoimmune disease by extrapolation of current research directions as well as thoughts on new methods of delivery of recombinant monoclonal antibodies. We predict that we will "cure" autoimmune pathology long before we understand the etiology. In the case of inflammatory bowel disease, as a model, and taking advantage of what is known on animal studies, we illustrate the progress that has been made in elucidating these pathways of destruction and speculate about possible therapeutic approaches.

An assay system to study migratory behavior of cranial neural crest cells in Xenopus.

An increasing number of genes are known to show expression in the cranial neural crest area. So far it is very difficult to analyze their effect on neural crest cell migration because of the lack of transplantation techniques. This paper presents a simple method to study the migratory behavior of cranial neural crest cells by homo- and heterotopic transplantations: Green fluorescent protein (GFP) RNA was injected into one blastomere of Xenopus laevis embryos at the 2-cell stage. The cranial neural crest area of stage 14 embryos was transplanted into the head or trunk region of an uninjected host embryo, and the migration was monitored by GFP fluorescence. The transplants were further examined by double immunostaining and confocal microscopy to trace migratory routes inside the embryo, and to exclude contaminations of grafts with foreign tissues. Our results demonstrate that we developed a highly efficient and reproducible technique to study the migratory ability of cranial neural crest cells. It offers the possibility to analyze genes involved in neural crest cell migration by coinjecting their RNA with that of GFP.

Role of cytomegalovirus infection in allograft rejection: a review of possible mechanisms.

Several lines of evidence indicate that viral infections, particularly with cytomegalovirus (CMV), play a role in the pathogenesis of solid organ allograft rejection. A diagnostic feature of acute rejection is infiltration of allograft parenchyma by lymphocytes, a process regulated by induction of adhesion molecules on vascular endothelial cells and their ligand on leucocytes. Data derived from biopsies of CMV-infected transplant recipients, as well as from experimental models of transplantation, indicate that CMV infection can result in an upregulation of such adhesion molecules, thereby facilitating the inflammatory process. Infection with CMV is also associated with an increased expression of MHC class II on multiple cell types. Since recognition of nonself MHC antigens is the major determinant of allograft rejection, an upregulation of these molecules could contribute to graft failure. Infection with CMV has also been implicated in the induction of smooth muscle proliferation and intimal thickening, both hallmarks of transplant atherosclerosis, which constitutes the most common cause of heart allograft failure. CMV can be classified into four, possibly five, different genotypes based on restriction length polymorphism of the envelope glycoprotein B gene; these genotypes may exhibit varied geographic and demographic frequency distributions and also differ in their pathogenicity and cell tropism. Further studies are needed to evaluate these issues and in particular the genetic contribution of the recipient to CMV modulation of rejection.

E7-specific cytotoxic T cell tolerance in HPV-transgenic mice.

The "high-risk" human papillomavirus type 16 (HPV 16) is associated with the development of cervical cancer. Although the viral gene products E6 and E7 are constitutively expressed in HPV 16-associated lesions and therefore appear as candidate antigens for a specific immune response, the immune system fails to produce an efficient defence against tumor outgrowth in affected patients. Keratinocytes are the natural target cells of HPV infection. To investigate the E7-specific immune response in vivo, we used transgenic mice expressing the oncogenes E6 and E7 of HPV 16 under the control of the keratin 10 promoter in the suprabasal layers of the epidermis. This expression pattern closely reflects the viral early gene transcription that is observed in low grade cervical intraepithelial lesions (CIN). The transgene product E7 does not induce an immune response in these transgenic mice. However, upon vaccination anti-E7 antibodies were produced without causing signs of autoimmune disease. In contrast, E7-specific cytotoxic T lymphocytes (CTL) were not detected after immunization. From these results we conclude that in K10 HPV 16 E6/E7 transgenic mice the E7 transgene expression induces specific immunological tolerance on the CTL level.