Syftet med denna studie är att teoretiskt pröva att integrera en etablerad metod för personlig utveckling, The Skilled Helper, med metoden Dynamisk Pedagogik och skapa en ny metod för en specifik tillämpning, personlig utveckling av ledare. Integrationen görs med hjälp av en etablerad metametod för metodutveckling. De bägge ingående metoderna värderas enligt fastställda kriterier. Samma kriterier används sedan för att värdera den nya metod som designas. Med detta har studien uppnått en jämförbarhet mellan de tre metoderna avseende parametrar som är centrala och relevanta för metoder och metodskapande. Studien skall besvara en rad olika frågeställningar såsom: Går det att skapa en integrerad ny metod förpersonlig utveckling baserat på av två befintliga metoder: The Skilled Helper och Dynamisk Pedagogik? Vad händer när man integrerar dem? Blir det konflikter eller synergieffekter mellan de bägge metoderna? Vad är kvar av Dynamisk Pedagogik? Den nya metoden som skapas, faller den inom ramen för etablerad ledarutveckling? Kan den kallas för en metod för ledarutveckling? Resultatet visar att metodintegrationen gick att genomföra då det förelåg en tillräckligt god grundläggande förenlighet mellan de två ursprungsmetoderna på en rad nyckelområden. Dock fanns kritiska vägval att göra vid design av den nya metoden, vilket gör att den nya metoden blev särskiljande från de bägge ursprungsmetoderna. Resultatet visar att det inte blir konflikter, efter som de vägval som behövde göras inte gav upphov till konflikt inom den nya metoden. Inte heller uppnås synergieffekter, då den nya metoden utformades för ett syfte som avvek från ursprungsmetodernas respektive syften. Resultatet visar slutligen att endast två av tre centrala förhållningssätt från Dynamisk Pedagogik finns kvar i den nya metoden som skapas, det självpedagogiska och det skapande förhållningssättet. Det tredje och mest centrala förhållningssättet, det samspelande, som bygger på att lärande sker i samspel med andra individer, kunde inte tillgodoses då den nya metoden enbart är utvecklad för individuell utveckling. Därför kan inte den nya metoden kallas att vara en variant av Dynamisk Pedagogik. I analysen diskuteras huruvida den nya metoden uppfyller de krav och önskemål som framställs i litteraturen på förändrad ledarutveckling och emotionell intelligens bland ledare. Den nya metoden visar sig kunna möta de flesta krav och önskemål som ställs men det går inte att påvisa om det ger den önskade effekten såsom förändrat ledarbeteende genom ökad självinsikt och självkännedom. Den nya metoden får i resultatet benämningen “Dynamisk Ledarutveckling” då metoden harmonierar både med innebörden av begreppet dynamisk och begreppet ledarutveckling. / <p>Författaren kan kontaktas på e-postadressen: titti.rudback@rudback.nu</p>

L’histoire naturelle du cancer implique des interactions entre la tumeur et les mécanismes de défense de l’hôte, tout particulièrement avec le système immunitaire adaptatif. Ainsi la transformation de cellules normales en cellules malignes peut engendrer l’expression d’antigènes tumoraux reconnus par les lymphocytes T. Plusieurs sous-populations de lymphocytes T (LT) CD4 contrôlent les réponses antitumorales, parmi elles, les LT CD4 helper de type-1 (Th1) jouent un rôle activateur majeur de l’immunité à médiation cellulaire antitumorale. Ils deviennent actifs grâce à la reconnaissance des peptides de 15 à 20 acides aminés dérivés d’antigènes tumoraux et présentés par les molécules HLA de classe II. Ils sont nécessaires à l’induction et la fonction des cellules effectrices dirigées contre les tumeurs notamment les lymphocytes T CD8 cytotoxiques (CTL). De plus la présence de lymphocytes CD4 Th1 infiltrant les tumeurs est souvent associée à un bon pronostic chez les patients. A l’aide d’un modèle in vitro chez l’homme et in vivo chez des souris transgéniques HLA, nous avons identifié quatre nouveaux peptides CD4 dérivés de la télomérase (TERT) un antigène de tumeur exprimé dans la majorité des cancers humains. Ces peptides appelés «Universal Cancer Peptide, UCP» se lient à la majorité des allèles HLA-DR et sont capables d’activer spécifiquement les LT CD4 de type-1. Des LT CD4 circulants spécifiques des UCP sont naturellement détectables dans plusieurs cancers humains mais absents chez des individus sains. Des clones T CD4 spécifiques des UCP générés à partir des lymphocytes de patients, produisent de forts taux d’IFN, TNF, et d’IL-2, cytokines associées à la polarisation Th1. L’analyse par ELISPOT IFN, de LT CD4 anti-UCP circulants au sein d’une cohorte de 84 patients atteints de cancers bronchiques métastatiques a montré la présence naturelle de ces lymphocytes chez 38 % des patients. De plus un effet bénéfique de la présence de cette réponse sur la survie globale a été observé chez les patients ayant une réponse clinique objective après chimiothérapie (13 vs 10 mois, P< 003). In vivo, l’immunisation de souris transgéniques HLA-A2/HLA-DR1 (Tg A2/DR1) avec les peptides UCP stimule des réponses T CD4 spécifiques caractérisées par une polarisation Th1. Nous avons montré que la présence in vivo de LT CD4 anti-UCP est nécessaire pour l’induction de réponses CTL antitumorales efficaces. Ainsi chez des souris co-immunisées en présence d’un peptide UCP, on observe un accroissement en nombre et de la qualité des réponses CTL proportionnellement à l’aide délivrée par les LT CD4 anti-UCP. L’induction de LT CD4 anti-UCP s’accompagne également d’une activation des cellules dendritiques in vivo via un mécanisme impliquant CD40L, IFN et GM-CSF. Dans un modèle de mélanome transplantable chez les souris Tg A2/DR1 nos résultats ont montré qu’une vaccination thérapeutique comportant un peptide UCP favorise un meilleur recrutement de CTL fonctionnels dans les tumeurs et améliore ainsi l’efficacité antitumorale du vaccin. Ces résultats confirment le rôle antitumoral majeur des lymphocytes CD4 Th1 et soulignent l’intérêt clinique de stimuler des réponses T CD4 spécifiques d’antigènes tumoraux de relevance clinique comme TERT. / Recent advances in immunology have now validated the concept of cancer immunosurveillance and the leading role of adaptative T cell immunity. Until a few years ago, antitumor CD8 T cell responses have been the most studied due to their direct cytotoxic activity on tumor cells. On the other hand, study of antitumor CD4 T cell responses are even more challenging because of the heterogeneity and plasticity of the various CD4 T cells subpopulations described. Among them, CD4 T helper type-1 cells (Th1), mainly characterized by the production of IFN, control the activation of antitumor cellular immunity. Thus, stimulation of specific CD4 Th1 cells may have a major interest for the development of anticancer immunotherapies. During this research thesis, we characterized novel HLA class II epitopes derived from a relevant tumor antigen, telomerase (TERT), and studied their capacities to stimulate specific CD4 Th1 cell responses. Using a method based on predictive immunology, we identified 4 peptides derived from TERT, referred as « Universal Cancer Peptides » (UCPs), enable to bind the most commonly found HLA-DR alleles in human. Using HLA-A2/HLA-DR1 transgenic mouse model, we first evaluated the in vivo immunogenicity of these peptides. Immunization of mice with UCPs induces high avidity specific CD4 T cells. The study of their polarization showed that UCP-specific CD4 T cells do not produce IL-4, -5, -10 or -17 cytokines, excluding a Th1, Treg or Th17 differentiation. In contrast, we measured high amount of IFN and IL-2 which characterize a Th1 pattern. The study of helper role allow us to demonstrate that CD8 peptide-based vaccinations in presence of UCPs enhance the efficacy of tumor specific CTL responses. Indeed, the intensity of these responses is strongly correlated with that of UCP-specific CD4 T cells induced in vivo. Furthermore, the stimulation of UCP-specific CD4 T cells promotes activation and IL-12 release by dendritic cells through a mechanism that involves IFN, GM-CSF and CD40L. We also demonstrated the antitumor efficacy of UCPs during a therapeutic vaccination in mice, as well as their capacity to foster the recruitment of specific CD8 T cells at the tumor site. In addition, the presence of naturally occurring UCP-specific CD4 T cell responses was found in different types of cancers such as leukemia, lung, colorectal or renal cancers. A study conducted in a cohort of 84 metastatic lung cancer patients revealed a synergistic effect of spontaneous UCP-specific CD4 Th1 and chemotherapy-treatment. Altogether, this study provides further evidences that stimulation of antitumor CD4 Th1 cells is a powerful method to improve cancer vaccines and also highlights the interest of TERT-derived UCPs for the innovative monitoring of antitumor CD4 T cell responses

The Tec kinase ITK is activated by TCR stimulation and also required for TCR downstream signaling. Previous studies have reported differential roles of ITK and another Tec family kinase RLK in CD4+ TH differentiation and effector function. However, these findings are confounded by the complex T cell developmental defects in Itk-/- mice. Furthermore, the function of ITK in tissue-resident T cells in the intestine and anti-viral immune response to a persistent infection has not been studied previously. In addition to T cells, recent studies have indicated an expression of ITK in ILC2, but not in other ILC subsets. Yet, the role of ITK in ILC2 has not been characterized. Here, I have examined the role of ITK and RLK in CD4+ TH subsets using a small molecule inhibitor PRN694. I found that PRN694 impaired TH1 differentiation in vitro, and PRN694 administration prevented TH1-mediated colitis progression in vivo. In an MHV68 infection model, Itk-/- mice failed to control viral replication in the intestine, while gut-homing of CD8+ T cells was greatly impaired. Finally, I found that ILC2 number was markedly reduced in the intestine of Itk-/- mice. Gut-specific defect of Itk-/- ILC2 is associated with a low availability of IL-2 in the intestine of Itk-/- mice. Collectively, these data suggest that ITK is important in T cell migration to the intestine and ILC2 homeostasis in the intestine, thereby contributing to the protective response to a latent virus and intestinal tissue homeostasis.

Le système immunitaire humain est majoritairement commandé par les cellules dendritiques et les lymphocytes T auxiliaires. Lorsque les cellules dendritiques détectent un pathogène, elles vont instruire les lymphocytes T auxiliaires afin qu’ils adoptent le phénotype approprié à la menace rencontrée. Les lymphocytes T auxiliaires peuvent être divisés en plusieurs sous-populations, caractérisées par la production de cytokines spécifiques. Chaque sous-population de lymphocyte T auxiliaire possède des fonctions propres et est impliquée dans l’élimination de pathogènes distincts. Si les réponses des lymphocytes T auxiliaires ne sont pas finement régulées, ils peuvent devenir pathogéniques, et dans ce cas, considérés comme cibles potentielles pour des thérapies. Dans ce contexte, j’ai concentré mon travail de doctorat sur l’étude de la diversité des sous- populations de lymphocytes T auxiliaires et de leur régulation. Premièrement, j’ai démontré que les cellules dendritiques activées par la TSLP sont capables d’induire la polarisation de lymphocytes T folliculaires. Ensuite, j’ai participé à la construction d’un modèle mathématique capable de prédire la réponse lymphocytaire T auxiliaire en fonction de signaux dérivés des cellules dendritiques. Ce modèle nous a permis d’identifier un rôle spécifique pour l’IL-12p70, dépendant du contexte IL-1, dans l’induction d’IL-17F sans IL-17A. Enfin, j’ai monitoré huit populations de lymphocytes T auxiliaires et folliculaires dans le sang périphérique de patients atteints de dermatite atopique traités par Dupilumab, une immunothérapie ciblant la sous-unité alpha du récepteur de l’IL-4 et j’ai pu montré que la diminution du pourcentage de lymphocytes Th17 correlait avec l’amélioration du score clinique EASI. Globalement, mon travail sur la diversité de phénotypes Th apporte une ressource mécanistique importante, avec une potentielle application en immunothérapie. / Human immunity is essentially driven by dendritic cells and T helper cells. When dendritic cells detect a pathogen, they will instruct T helper cells to adopt the adapted phenotype for the specific threat encountered. T helper cells are subdivided in multiple subsets, characterized by particular sets of cytokines. Each T helper subset has specific functions and is involved in the clearance of distinct pathogens. If T helper responses are not precisely regulated, they can become pathogenic, in this case T helper pathways can be considered as potential targets for therapy. In this context, I focused my PhD work on studying T helper cell subset diversity and regulation. First, I demonstrated the ability of TSLP-activated dendritic cell to induce T follicular helper cell polarization. Then I participated in building a mathematical model capable of predicting T helper cell response to dendritic-cell derived signals. This model allowed us to identify the specific role of IL-12p70, in an IL-1 context, to induce IL-17F without IL-17A. Finally, I monitered eight T helper and T follicular helper cell populations in peripheral blood from atopic dermatitis patients treated with Dupilumab, an immunotherapy targeting the IL-4 receptor alpha subunit, and was able to show a correlation between decrease of Th17 cell percentage and improvement of EASI clinical score. Overall, my work on Th phenotype diversity provides key mechanistic insight with potential application in immunotherapy.

In South African secondary schools there are learners who undergo a daily struggle with social and emotional problems. The problems learners struggle with include problems like drug and alcohol abuse, suicide, domestic violence, peer pressure, anorexia, bulimia, stress, bullying, and many more. These problems often result in learners experiencing a great deal of pressure. They sometimes feel hopeless as they fail to find suitable solutions for their problems. They often feel alone and as though there is no one whom they can share their problems with and who truly understands. A Peer Helper Programme is a programme that focuses on training a selective group of learners to be peer helpers. A peer helper is someone who understands or someone of more or less the same age as the person seeking for help, has empathy, good listening and communication skills, and offers help and understanding in times of need. A literature study has been undertaken to give the precise description of the concept of peer help, to determine the task and function of a peer helper and to establish what exactly the training of a peer helper should encompass. The results obtained from this information allowed the setting of guidelines for the implementing of a peer helper programme for the effective training of peer helpers. An empirical study was executed to establish the nature and scope of the problems learners in secondary schools in the Klerksdorp school district experience and their needs concerning peer helping. From this study it was concluded that a need exists for peer helping programmes as well as guidelines for the design and implementation of a peer helper programme. Questionnaires were used and the following can be concluded from the investigation: There is an existing need for a peer helper programme as learners who experience problems will rather share this with a peer before telling an older person. A set of guidelines need to be put into place for the implementation of a peer helper programme. To conclude the recommendation is made at the end of this study that a peer helper programme needs to be implemented in every school in the various school districts and that it should stand under the management of the school principle and the assistance of the guidance teacher. / Thesis (M.Ed.)--North-West University, Potchefstroom Campus, 2006.

This study was designed to determine the effectiveness of a filial/play therapy training model with high school juniors and seniors enrolled in a Peer Assistance and Leadership program (PALs). Filial/play therapy is an intervention that focuses on strengthening and enhancing adult-child relationships. The high students are trained to be a therapeutic change agent for primary school children identified as having adjustment difficulties by utilizing basic child-centered play therapy skills in weekly play sessions with young children. Specifically, this study is designed to determine the effectiveness of filial therapy in increasing: 1) the high school students' observed empathic behavior with young children, 2) the high school students' observed attitude of acceptance toward young children, 3) the high school students' observed ability to allow self-direction in young children, and 4) the high school students' observed level of involvement with young children. The experimental group, consisting of 16 volunteer high school students enrolled in a PALs class for high school credit, received a total of 24 weeks of filial/play therapy didactic training, application, and supervision for the playtimes they conducted with pre-kindergarten/kindergarten students identified with adjustment difficulties. The comparison group consisted of 15 volunteer high school students enrolled in a PALs class for high school credit. The comparison group received the standard PALs class curriculum. All students were videotaped playing with a young child 4 to 6 years of age before and after the training as a means of measuring empathic behavior with young children. An Analysis of Covariance revealed statistically significant findings in all four hypotheses. Specifically, the experimental group of high school students exhibited statistically significant increases in empathic interactions with young children when compared to the comparison group. The experimental group also exhibited statistically significant increases in communication of acceptance of young children's feelings and behaviors, acceptance and behavioral willingness to follow young children's lead rather than attempt to control their behavior, and attention to and participation in young children's play. This study supports the use of filial/play therapy as an effective training model for increasing high school students' empathic behavior with young children. Filial/play therapy offers significant possibilities for training high school students in a developmentally appropriate model for working with young children identified with school adjustment difficulties, in order to prevent future problems.

The Early Growth Response genes 2 and 3 (Egr2/3) are zinc finger transcription factors that play an important role in the immune system. These transcription factors have reported functions in T cell receptor signaling, differentiation of effector T cell subsets and the development of lupus-like autoimmune diseases. Using CD2-Egr2-/- Egr3-/- mouse model, I investigate the development of inflammation pathology, differentiation of T follicular helper (Tfh) cells and the formation of germinal centers (GC) following viral challenge within these mice. The onset of inflammation pathology in CD2-Egr2-/- Egr3-/- mice was discovered to correlate with high levels of pro-inflammatory cytokines in the serum and the development of autoimmune diseases as previously reported by Li et al, 2012. Most importantly, a novel role for the Egr2/3 genes in the differentiation of T follicular helper (Tfh) cells was identified. Tfh cells are responsible for T cell dependent antibody immune response in the GC. They support the differentiation of GC B cells into plasma cells producing long lived high-affinity isotype-switched antibodies and memory B cells. Tfh cell differentiation is regulated by Bcl6 however; the regulators of Bcl6 during Tfh differentiation remain largely unknown. We have now discovered that Egr2/3 genes are required for Bcl6 expression during Tfh cell differentiation. In the absence of the Egr2 and 3 genes, Tfh cell differentiation is severely impaired and GC formation and functions were defective in response to Vaccinia Virus Western Reserve strain (VVWR) infection. Further investigation revealed that Egr2 regulated Bcl6 expression in a Tfh-specific manner as adoptive transfer of WT CD4+ T cells into Egr2-/- Egr3-/- mice was able to rescue Bcl6 expression, Tfh differentiation and GC formation. When the molecular mechanism of how Egr2 regulated Bcl6 was investigated, it was uncovered that Egr2 directly bound to the promoter region of Bcl6 gene in CD4 T cells to regulated Bcl6 expression. Indeed constitutive expression of either Egr2 or Bcl6 in CD2-Egr2-/- Egr3-/- CD4+ T cells rescued Tfh cell differentiation and GC formation. Our results inferred that the Egr2/3 genes are essential for Tfh differentiation and GC formation by regulating Bcl6 expression in CD4 T cells under Tfh condition. Our studies thus suggest that the Egr2/3 genes are paramount for minimising immunopathology and are also critical for efficient antibody production by regulating Tfh cell differentiation.

Staphylococcus aureus pathogenicity island SaPI1 is a genomic element that is mobilized and transduced at high frequency by helper phage 80α. SaPI1 encodes a small terminase protein that belongs to the phage small terminase subunit family. The presence of SaPI1-encoded small terminase suggests that it plays a role in SaPI1-specific packaging into transducing particles by complexing with the 80α large terminase subunit and redirecting recognition to a pac site on SaPI1 DNA from 80α DNA. The effects of deleting the small terminase genes in SaPI1 and in a prophage copy of 80α are consistent with this hypothesis. Induction of the 80α small terminase deletion mutant produces wild type levels of SaPI1 transducing particles, demonstrating that SaPI1 small terminase can replace that of 80a in SaPI1 packaging. Southern blot analysis of virion DNAs isolated from the deletion mutants confirms that SaPI1 redirects packaging of its DNA into SaPI1-sized capsids.

T follicular helper cells (T-FH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in T-FH. Paradoxically, T-FH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased T-FH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in T-FH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in T-FH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of T-FH, other mechanisms that have been linked to T-FH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance T-FH function in HIV infection include lack of an established phenotype for memory T-FH as well as limited understanding of the relationship between peripheral T-FH and lymphoid tissue T-FH. Interventions to augment T-FH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.

Protection from influenza A virus (IAV) challenge requires switched, high affinity Abs derived from long-lived memory B cells and plasma cells. These subsets are generated in germinal centers (GCs), hallmark structures of T helper cell-driven B cell immunity. A full understanding of the acute and persistent GC B cell reaction following respiratory IAV infection is lacking, as is the characterization of IAV-induced T follicular helper (TFH) cells that support GCs. Additionally, it remains unclear as to whether IAV-induced GC B cells are subject to control by regulatory T cells (Tregs). To address this, GC B cell and TFH cell responses were analyzed in mice following pulmonary challenge with IAV. Studies demonstrated that marked GC reactions were induced in lung-draining lymph nodes (dLNs), lung, spleen and nasal-associated lymphoid tissue (NALT), although the magnitude, kinetics, and isotype switching patterns of the response was site-specific, and largely depended on the magnitude of IAV-induced TFH cell populations. TFH cell magnitude peaked prior to that of GC B cells in all tissues, and TFH cells purified from dLNs generated IL-21 and IFN-gamma upon activation, although CD4+CXCR5- T effector cells produced higher levels of all cytokines. IgA+ GC B cells were infrequent in most sites, but composed a significant subset of the switched GC population in NALT. Further, splenectomized mice withstood a lethal recall challenge, suggesting the spleen to be unnecessary for long-term protection. Additionally, GC B cell populations were analyzed at distal time points to assess the understudied, persistent GC B cell response after IAV infection. Our analysis demonstrated that persistent GC B cell populations in mouse lungs directly correlated with infectious dose, pathogenicity of the virus, as well as the presence of long-term CD4+ T cell help. Finally, experiments showed that Tregs contribute to the control of GCs induced in the spleen by IAV challenge. This was demonstrated by a marked increase in the number of total and switched GC B cell numbers when Tregs were either depleted or disrupted in vivo proximal to IAV exposure.