Este estudo baseou-se no acompanhamento, por parte da pesquisadora como analista judiciária, de quatro casos de adoção de crianças entre quatro e 10 anos de idade, tramitados na Segunda Vara da Infância e Juventude de Recife, ao longo do ano de 2013. Nesses casos, constatamos a dificuldade de os adotandos filiarem-se às mães adotivas, às quais se gerou grande sofrimento, enquanto se aproximaram afetivamente dos pais adotivos sem aparentes percalços. Por tal razão, a fim de contribuir para o trabalho desenvolvido nas adoções de crianças acima de quatro anos (aqui referidos como adoções de criança maior), preparando os adotandos e auxiliando os adotantes no processo de filiação, buscamos identificar as particularidades dessa filiação. Além do mais, analisamos o modo de se vivenciarem a maternidade e a paternidade nos estágios de convivência e, ainda, de a relação do casal quanto ao desejo de adoção, relacionar-se com a interação da criança com as figuras parentais adotivas. Para isso, realizamos uma pesquisa de abordagem psicanalítica, analisando os relatos de acompanhamento dos estágios de convivência. Como resultado, em relação às crianças adotadas, constatamos que a precariedade na vivência do luto das imagos parentais prejudica o reinvestimento afetivo nas novas figuras maternas. Já em relação às famílias adotivas, percebemos que as dificuldades na vivência do luto do filho biológico interferem na filiação adotiva. Especificamente, para as mães adotivas, é necessário o luto do lugar de mãe como o lugar do objeto de amor primordial do filho, uma vez que, pelo desenvolvimento do adotando, a criança demandará um modelo de relação diferente daquela construída com infantes. Diante de tais constatações, esperamos contribuir para a construção de novos conhecimentos que embasem o trabalho de preparação das famílias adotivas, fundamental para o sucesso na adoção. / This study was based on the attendance, by this reasearcher as a judiciary analist, in four adoptions cases of children between four and ten years old, prosecuted at the Recifes Secound Childhood and Adolescece Court, along the year of 2013. On these cases, we verified the adoptees difficulty to filiate with the adoptive mothers, wich caused great suffering, while they affectively approached the adoptive fatherss without any apparent setbacks. For that reason, to contribute to the development of the work whith older than four year old childrens adoption (here refered as older child adoption), preparing the adoptees and assisting the adoptive parents on the filiation process, we sought to identify these filiations particularities. Furthermore, we analyzed how the maternity and paternity was experienced on the adaptation period and, more, and the relation of the couple regarding the will to adopt related to the childs interaction with the adoptive figures. Thereunto, we conducted a psychoanalytic approachs reaseach, analysing adaptation periods attendance reports. As results, regarding the adoptive children, we verified that the precariousness on experiencing the parental imagos mourning affects the emotional reinvestment upon the new maternal figures. As for the adoptive families, we noticed that the difficulties experiencing the biological childs mourning interferes on the adoptive filiation. Especially, for the adoptive mothers, it required mourn being a mother as being the sons primary love object, since, because of the childs development, he will demand a different relationship pattern than the one experienced with a baby. Upon the findings, we hope to contribute to the development of new knowledge to base te adoptive families preparation, essential to the adoptions success.

Das Ausmaß der permanenten klinischen Defizite bei Multiple-Sklerose-Patienten entsteht durch axonale Schädigung und axonalem Verlust. In dieser Studie wird eine entscheidende Rolle des niedrigaffinen Neurotrophinrezeptors p75NTR in Bezug auf axonale Schädigung in der experimentellen autoimmunen Encephalitomyelitis (EAE) gezeigt. Nach EAE Induktion per aktiver Immunisierung mit dem Myelin-Oligodendrozyten-Glykoprotein-Peptid MOG35-55 zeigten p75NTR KO Mäuse einen verschlechterten Krankheitsverlauf, stärkere Demyelinisierung und erhöhte axonale Schädigung. Um festzustellen, ob die erhöhten Defizite von einer aggressiveren Inflammation oder von einem vulnerableren zentralen Nervensystem (ZNS) stammen, wurden das Immunsystem während der peripheren Krankheitsentstehung und der darauffolgenden Krankheitsphase und Zellen des ZNS in vivo, ex vivo und in vitro untersucht. Es wurde kein Unterschied in der Qualität der Inflammation mit Hilfe von immunohistochemischen, durchfluss-zytometrischen, ELISA- und mRNA-Analysen gefunden, wodurch eine entscheidende Rolle der untersuchten Immunzellpopulationen ausgeschlossen werden kann. Notzdestrotrotz legt die konstitutive Expression von p75NTR auf B-Zellen eine Rolle für p75NTR während der Generation der Immunantwort innerhalb der Lymphknoten nahe, da p75NTR KO Mäuse von Anfang an einen erhöhten Krankheitsverlauf zeigten. Um die Effekte der p75NTR-Defizienz während des peripheren Primings zu umgehen, wurde die EAE auch durch adoptiven Transfer eines encephalitogenen MOG35-55-spezifischen T-Zell-Klones in p75NTR KO und Wildtyp (wt) Mäusen iduziert. Sie zeigten ähnliche Inzidenz, Beginn und Kinetik der Krankheit. Ein vergleichbares Ausmaß und eine vergleichbare Qualität der Inflammation wurde mit immunohistochemischen und mRNA-Analysen in beiden Mausstämmen am Höhepunkt der Krankheit gefunden. Nichtsdestotrotz leideten p75NTR KO Mäuse an signifikant erhöhten Krankheits-Scores in der chronischen Phase infolge von erhöhtem axonalen Schaden und Verlust. Dies deutet auf eine protektive Rolle von p75NTR im ZNS hin. In dieser Arbeit wird gezeigt, dass Astrozyten, aber nicht Mikroglia, p75NTR konstitutiv exprimieren. Jedoch wurde keine p75NTR-mediierte Regulation von Cytokinen/Chemokinen und der Produktion von reaktiven Sauerstoff-Spezies in vitro gefunden. Aktive Immunisierung von Knochenmark-Chimären, in denen nur Immun- oder ZNS-Zellen einen funktionierenden p75NTR tragen, bestätigen diese Resultate. Während p75NTR KO in wt- und wt in p75NTR KO-Chimären im Vergleich zu wt in wt-Chimären unter einem stärker ausgeprägten Krankheitsverlauf am Höhepunkt der Krankheit leideten, zeigten nur wt in p75NTR KO-Tiere erhöhten axonalen Schaden und Verlust. Zusammengefaßt deuten diese Daten darauf hin, dass p75NTR-Defizienz zu einer aggressiveren peripheren Immunantwort führt (namentlich durch B-Zellen). Desweiteren hat p75NTR auch neuroprotektive Eigenschaften innerhalb des ZNS (namentlich auf Neuronen) unter experimentellen inflammatorischen Bedingungen im ZNS.

Made available in DSpace on 2017-06-01T18:08:27Z (GMT). No. of bitstreams: 1 dissertacao_licelia_martins.pdf: 797848 bytes, checksum: c8efc4cc47122fa4e604ddbc25ab6501 (MD5) Previous issue date: 2010-04-05 / Desde el punto de vista psicológico, la adopción no siempre aparece como una solución para el problema del abandono. A menudo, los resultados de la adopción en un fracaso, poniendo en peligro el desarrollo saludable de los niños y que causa malestar y la infelicidad que relámpago a todos los involucrados en este proceso. Son varios los factores responsables de este fracaso. Uno de los más señalados en la clínica es la insuficiencia o la falta de unión entre los padres de miembros y los niños adoptados. El objetivo de este estudio es reflexionar sobre los dilemas y los factores que obstaculizan y / o prevenir la formación de enlaces en la filiación adoptiva. Se trata de una investigación teórica en la que debatir el concepto de autores de diferentes corrientes empate: francesas, estadounidenses y argentinos. Luego problematizar la formación del enlace en la adopción, teniendo en cuenta los factores que dificultan o impiden el cincel de este enlace. Hemos visto que el valor asignado a los lazos de sangre, las expectativas inadecuadas sobre la nueva Constitución mediante la adopción de la familia, los mitos y las fantasías y la ausencia de duelos anteriores se encuentran entre los factores que dificultan o impiden el vínculo entre la formación de los padres y los niños adoptados. El deseo de un niño por los candidatos para la adopción y el deseo infantil de ser afiliado son esenciales en la creación de la relación / Do ponto de vista psicológico, nem sempre a adoção configura-se como uma solução para o problema do abandono. Muitas vezes, a adoção resulta em um fracasso, comprometendo o desenvolvimento saudável da criança e causando um mal estar e infelicidade que acometerá a todos envolvidos nesse processo. Vários são os fatores responsáveis por tal fracasso. Um dos mais identificados na clínica é a falha ou inexistência do estabelecimento de vínculo de filiação entre pais e filhos adotivos. Assim, o objetivo desse estudo é refletir sobre os impasses e fatores que dificultam e/ou impedem a formação do vínculo na filiação adotiva. Trata-se de uma pesquisa teórica na qual discutimos a noção de vínculo em autores de diferentes correntes: francesa, americana e argentina. Em seguida problematizamos a formação do vínculo na adoção, considerando os fatores que dificultam ou impedem a formão desse vínculo. Apresentamos algumas vinhetas clínicas no sentido de contextualizar os impasses vividos quando o desejo de adotar não está associado ao de ter filho. Vimos que o valor atribuído ao vínculo de sangue, as expectativas inadequadas em torno da nova constituição familiar através da adoção, os mitos e fantasias e a não elaboração dos lutos anteriores estão entre os fatores que dificultam ou impedem a formação vincular entre pais e filhos adotivos. O desejo de um filho pelos candidatos à adoção e o desejo das crianças de serem filiadas são essenciais na constituição do vínculo

Made available in DSpace on 2017-06-01T18:08:55Z (GMT). No. of bitstreams: 1 marciana_silva_souza.pdf: 1238261 bytes, checksum: a748d2db001ecd8986c24fd84bcf740e (MD5) Previous issue date: 2014-11-18 / The adoption issue is being debated currently in the media (articles, interviews, novels, movies), colleges (monographs, dissertations, theses, books, scientific events), and society (enactment of laws, formation of support groups and also a national association of these groups). Efforts have been made to spread a new culture of adoption, which prioritizes children s rights and needs. Among these, first of all, the right to know about their origin. Adoption has, as the most important of its principles, child s integration in new families, which gives them the possibility of a new identity reconstruction, once they have the knowledge about their origin, consequently supporting a new pleasant family interaction. Their adaptation in a new place, purpose the establishment of new family bands, which is going to need different and new emotional components: love, affection, attention, commitment and above all of it, respect to their progress history. This research has a general objective: to understand and identify, on adopted adults perspective, if there were changes, and what those changes were, what happened in their lives after that they had knowledge about their origin. Specifically the intention is: to understand how this knowledge was taken, and the importance it has in the adoptees identity organization; to comprehend how adoptees started to perceive their new parents and themselves; what their position when it comes to myths, fears, beliefs and prejudices is, permeating the social imaginary. To achieve the proposed objective, we opted for a qualitative methodology. Eight adults were interviewed, both genders, those who had knowledge about their origin, and the context was analyzed based on the thematic technique of analysis content. Results indicate that: 1) although varied the age that they became aware of their origin, the participants consider essential that knowledge and propose that every adopted child has this right; 2) motivations for child adopting vary, prevailing financial difficulties; 3) there are different reactions between those who early knew their condition and those who got this piece of information when they were teenagers; 4) despite losses, the majority was satisfied with their adoptive family, indicating affection feelings, gratitude and recognition of their importance for survival and formation of their personality; 5) they were against prejudice and myths that pervade the condition of adoptive person; It s expected to contribute, aiming to highlight the issue, seeking to stimulate a greater awareness on the part of society to overcome the myths and prejudices that still roam the adoption. / O tema adoção está em debate, atualmente, tanto na mídia (reportagens, depoimentos, novelas, filmes), na academia (monografias, dissertações, teses, livros, eventos científicos), como na sociedade (promulgação de leis, formação de grupos de apoio e uma associação nacional desses grupos). Esforços têm sido feitos para difundir uma nova cultura da adoção em que se priorizem as necessidades e os direitos da criança. Entre estes se encontra o de saber sobre sua origem. A adoção tem como um dos fundamentos a ideia de que a integração de uma criança a uma nova família abre-lhe possibilidades para a reconstrução de sua identidade, a partir do conhecimento de sua origem, favorecendo, consequentemente, uma interação familiar mais satisfatória. Sua colocação em um novo lar pressupõe o estabelecimento de inéditas redes de relações, as quais irão necessitar de diversos componentes emocionais a serem dispensados à criança, como: amor, carinho, atenção, comprometimento e respeito diante de sua história pregressa. A presente pesquisa tem como objetivo geral identificar, na perspectiva de filhos adotivos adultos, as reações e as mudanças ocorridas na sua vida após o conhecimento de sua origem. Especificamente almeja-se compreender: como se deu esse conhecimento; sua importância na organização da identidade do(a) filho(a) adotivo(a); como esses filhos passaram a perceber seus pais adotivos bem como a si mesmos; como se posicionam frente a mitos, medos, crenças e preconceitos que permeiam o imaginário social. Para alcançar os objetivos propostos optou-se pela metodologia qualitativa. Foram entrevistados oito adultos, de ambos os sexos, que tinham conhecimento de sua origem, e os dados obtidos foram analisados com base na técnica da análise de conteúdo temática. Os resultados indicam que: 1) embora tenha variado a idade em que tomaram conhecimento de sua origem, os participantes consideram fundamental esse conhecimento e propõem que toda criança adotada tenha esse direito; 2) as motivações para a entrega da criança variaram, predominando as dificuldades financeiras; 3) existem diferenças nas reações entre aqueles que souberam de sua condição desde cedo e os que souberam na adolescência ou vida adulta; 4) apesar das perdas sofridas, a maioria se mostrou satisfeita com a família adotiva, demonstrando sentimentos de afeto, gratidão e reconhecimento de sua importância para sua sobrevivência e formação da sua personalidade; 5) todos se posicionaram contra os preconceitos e mitos que perpassam a condição de filho(a) adotivo(a). Espera-se contribuir para dar visibilidade à causa, buscando estimular uma maior conscientização por parte da sociedade para a superação dos mitos e preconceitos que ainda rondam a adoção.

Made available in DSpace on 2017-06-01T18:09:00Z (GMT). No. of bitstreams: 1 carolina_mendonca_muniz_albuquerque.pdf: 463447 bytes, checksum: 2a3b57496270cc79cba74128f7e31cbf (MD5) Previous issue date: 2016-04-01 / This study was based on the attendance, by this reasearcher as a judiciary analist, in four adoptions cases of children between four and ten years old, prosecuted at the Recife s Secound Childhood and Adolescece Court, along the year of 2013. On these cases, we verified the adoptee s difficulty to filiate with the adoptive mothers, wich caused great suffering, while they affectively approached the adoptive fatherss without any apparent setbacks. For that reason, to contribute to the development of the work whith older than four year old children s adoption (here refered as older child adoption ), preparing the adoptees and assisting the adoptive parents on the filiation process, we sought to identify these filiations particularities. Furthermore, we analyzed how the maternity and paternity was experienced on the adaptation period and, more, and the relation of the couple regarding the will to adopt related to the child s interaction with the adoptive figures. Thereunto, we conducted a psychoanalytic approach s reaseach, analysing adaptation periods attendance reports. As results, regarding the adoptive children, we verified that the precariousness on experiencing the parental imago s mourning affects the emotional reinvestment upon the new maternal figures. As for the adoptive families, we noticed that the difficulties experiencing the biological child s mourning interferes on the adoptive filiation. Especially, for the adoptive mothers, it required mourn being a mother as being the son s primary love object, since, because of the child s development, he will demand a different relationship pattern than the one experienced with a baby. Upon the findings, we hope to contribute to the development of new knowledge to base te adoptive families preparation, essential to the adoptions success. / Este estudo baseou-se no acompanhamento, por parte da pesquisadora como analista judiciária, de quatro casos de adoção de crianças entre quatro e 10 anos de idade, tramitados na Segunda Vara da Infância e Juventude de Recife, ao longo do ano de 2013. Nesses casos, constatamos a dificuldade de os adotandos filiarem-se às mães adotivas, às quais se gerou grande sofrimento, enquanto se aproximaram afetivamente dos pais adotivos sem aparentes percalços. Por tal razão, a fim de contribuir para o trabalho desenvolvido nas adoções de crianças acima de quatro anos (aqui referidos como adoções de criança maior ), preparando os adotandos e auxiliando os adotantes no processo de filiação, buscamos identificar as particularidades dessa filiação. Além do mais, analisamos o modo de se vivenciarem a maternidade e a paternidade nos estágios de convivência e, ainda, de a relação do casal quanto ao desejo de adoção, relacionar-se com a interação da criança com as figuras parentais adotivas. Para isso, realizamos uma pesquisa de abordagem psicanalítica, analisando os relatos de acompanhamento dos estágios de convivência. Como resultado, em relação às crianças adotadas, constatamos que a precariedade na vivência do luto das imagos parentais prejudica o reinvestimento afetivo nas novas figuras maternas. Já em relação às famílias adotivas, percebemos que as dificuldades na vivência do luto do filho biológico interferem na filiação adotiva. Especificamente, para as mães adotivas, é necessário o luto do lugar de mãe como o lugar do objeto de amor primordial do filho, uma vez que, pelo desenvolvimento do adotando, a criança demandará um modelo de relação diferente daquela construída com infantes. Diante de tais constatações, esperamos contribuir para a construção de novos conhecimentos que embasem o trabalho de preparação das famílias adotivas, fundamental para o sucesso na adoção.

Made available in DSpace on 2017-06-01T18:29:22Z (GMT). No. of bitstreams: 1 sheila_speck.pdf: 5164980 bytes, checksum: 94253f69656f0d73d9fffdf7bb4da98b (MD5) Previous issue date: 2013-08-16 / The adoption context of older children faces confrontation between past and present. It is made of stories that intersect and merge into the new gathering. Thereby, we highlight the importance of considering such dynamics and the resulting effects from old bonds on the new adoptive filiation construction. From this perspective, we have done a meta-analysis study of the dissertation The Process of Becoming a Father, a Mother, and Children in the Adoption of Older Children. Based on accounts collected along the judicial dismissal period and in the adjustment period follow up, we were able to reconstruct part of the children s and the adoptive families stories and, then, conduct a clinical analysis from a psychoanalytical bias. The present study has demonstrated that the old parental imagos and the marks from the previous story never cease to re-inscribe themselves. It has also been shown that distressing situations from the prospective adopted children s past trigger defenses and interfere in the new affective bonds. This study has pointed out the need to consider the prospective adopted child s previous life and also the importance of the adjustment period, since the new filiation construction has its start during this time. / No contexto da situação adotiva de crianças maiores há um confronto entre passado e presente, são histórias que se cruzam e se fundam a partir de um novo encontro. Desse modo, destacamos a importância de se considerar essa dinâmica e os efeitos decorrentes dos antigos laços na construção da nova filiação adotiva. Partindo dessa perspectiva, realizamos um estudo de meta-análise do trabalho de dissertação sobre: O processo de Tornar-se Pai, Mãe e Filhos na Adoção de Crianças Maiores . Com base nos depoimentos coletados no decorrer do período da destituição judicial e do acompanhamento do estágio de convivência, pudemos reconstruir parte da história das crianças, da família adotante, e realizar uma análise clínica pelo viés psicanalítico. O presente estudo evidenciou que as antigas imagos parentais e as marcas da história anterior não cessam de se (re)inscrever, e que as situações angustiantes do passado das crianças em processo de adoção desencadeiam defesas e interferem nos novos laços afetivos, ressaltando a necessidade de se considerar a vida anterior da criança em adoção. Revelou ainda, a importância que deve ser conferida ao estágio de convivência, visto que, a construção da nova filiação tem seu início nesse período.

Les mères adoptantes à l’international vivent généralement un grand bonheur au moment de la rencontre avec leur enfant, car leur fort désir de fonder une famille ou de l’agrandir se concrétise (Duvert, 2007). Or, la période d’adaptation suivant l’arrivée de l’enfant peut être difficile, d’autant plus que plusieurs enfants adoptés à l’international présentent des besoins spéciaux (Dartiguenave, 2012; Martin et al., 2016). Le soutien apporté par le réseau immédiat est donc important (Jeannet, 2017). L’objectif de la présente étude est de documenter le rôle du réseau immédiat (famille, amis, autres parents adoptants, collègues, voisins) dans le soutien apporté aux mères adoptantes à l’international, suivant les trois premières années de l’arrivée de l’enfant. Douze entrevues individuelles semi-structurées ont été réalisées avec des mères ayant adopté au cours des trois dernières années. À leur arrivée, les enfants étaient âgés entre neuf mois et quatre ans et demi. Les thèmes de l’entrevue sont : les besoins des mères, la composition de leur réseau immédiat, les formes de soutien reçu et leur satisfaction du soutien. Précisons que le cadre conceptuel est celui du soutien social. L’analyse thématique dévoile que les besoins des mères sont d’avoir du répit, d’être écouté, encouragée et respectée dans leur rôle de parent adoptant. Leur réseau immédiat a surtout un rôle de soutien émotionnel et informationnel et occasionnellement un rôle d’accompagnement social. Le répit et l’aide concrète sont rares. Les mères rapportent que leurs principales sources de soutien sont leurs parents et leur meilleure amie. Les parents adoptants qu’elles fréquentent se distinguent par leur excellente compréhension de l’adoption. La majorité des mères sont satisfaites du soutien reçu. Leurs insatisfactions, peu nombreuses, sont le manque de répit et les difficultés de leurs proches non-adoptants à comprendre l’adoption. La discussion révèle que certaines mères sont inconfortables et réticentes à demander du soutien, car elles veulent être autonomes et craignent de déranger. Or, il ressort que les mères les mieux soutenues et satisfaites du soutien sont celles qui expriment leurs besoins de soutien. Quelques recommandations sont suggérées : accompagner les mères adoptantes à exprimer leurs besoins et informer le réseau immédiat sur la parentalité adoptive internationale. / International adoptive mothers generally experience great happiness when they meet their child, because their strong desire to start a family or expand it becomes a reality (Duvert, 2007). However, the adjustment period following the arrival of the child can be difficult, even more so when many children adopted internationally have special needs (Dartiguenave, 2012; Martin et al., 2016). The support provided by the immediate network is therefore important (Jeannet, 2017). The objective of this study is to document the role of the immediate network (family, friends, other adoptive parents, co-workers, neighbours) in providing support to mothers who adopted internationally, in the first three years after the child’s arrival. Twelve semi-structured one-on-one interviews were conducted with mothers who adopted in the past three years. At their arrival, the children were between nine months and four and a half years old. The themes of the interview are: adoptive mothers’ needs, the composition of their immediate network, the forms of support received and their satisfaction of support. The conceptual framework is that of social support. A thematic analysis reveals that these mothers’ needs are to have respite, to be listened to, to be encouraged and to be respected in their role as adoptive parents. Their immediate network has a support role that is mainly emotional and informational and occasionally social. Respite and concrete help are rare. The mothers reported that their main sources of support are their parents and their best friend. The adoptive parents stand out within their immediate network in that they have an excellent understanding of adoption. The majority of the mothers are satisfied with the support received. Their dissatisfactions, though few, are the lack of respite and the difficulties of their non-adoptive relatives to understand adoption. The discussion underscores that some mothers are uncomfortable and reluctant to ask for support because they want to be independent and they fear bothering others. However, it emerged that the mothers who are the most supported and satisfied with the support are those who express their needs for support. Some recommendations are suggested: accompanying adoptive mothers in expressing their needs and informing the immediate network about international adoptive parenthood.

Given the general challenges associated with finding alternative care for an increasing number of orphans and vulnerable children (OVCs) in Zimbabwe, adoption appears to be an appropriate option. In practice adoption appears is one of the alternative forms of child care and ye it t has not received the necessary research attention. This study was aimed at developing an in-depth understanding of the challenges experienced by adoptive parents in the adoption of OVCs in Zimbabwe and the support system available for them in managing such challenges using the ecological systems theory. A qualitative research approach which was designed from exploratory, descriptive and contextual research designs to understand the challenges experienced by adoptive parents in the adoption of OVCs in Zimbabwe was adopted, with purposive and snowball sampling techniques used to identify and recruit a sample of eight parents who have undergone the process of adoption. Data was collected by means of semi-structured interviews guided by an interview guide and analysed according to Braun and Clarke’s six steps of qualitative data analysis. Trustworthiness of this study was evaluated according to its credibility, transferability, dependability and confirmability as proposed by Guba and Lincoln while relevant ethical principles were upheld throughout the entire duration of the study. The findings revealed a variety of socio-demographic features of adoptive parents as well as several challenges and experiences which are presented in a form of 10 themes and 13 subthemes in this report. Conclusions are drawn based on the research process and the research findings from which the recommendations are proposed for research, practice and training and education. / Social Work / M. A. (Social Work)

Currently, in most situations, the autologous immune system is unable to eradicate the residual leukemic burden persisting after chemo-radiotherapy, but a balance can be established between leukemic and immune cells leading to a clinical remission for several months or years. If this balance is broken, a clinical relapse can occur. The high incidence of relapses in human cancers demonstrates the frequent inefficacy of the immune system to control these residual cells. In this context, allogeneic hematopoietic stem cell transplantation (HSCT) has been proven to be the most effective way to reinforce the immune reaction against leukemia, graft-versus-leukemia (GVL) effect and, so, achieve a definitive eradication of the residual disease in a significant proportion of patients. Indeed, the whole concept of HSCT evolved from an organ transplant concept (to replace a defective ill organ with a new healthy one) to the concept of creating an extraordinary immunotherapeutic platform in which the donor immune system contributes to the eradication of the residual leukemic cells. Thus, the past and present issues remain those of finding the best immunomodulatory modalities to achieve a full engraftment, a powerful GVL effect and no or moderate graft-versus-host disease (GVHD). Different ways to reach this goal, such as post transplant cytokine modulation, specific or global cellular depletion of the graft and post transplant global or specific donor immune cell add-backs, are still extensively studied. Nevertheless, the persistent high relapse rate (RR) observed in leukemia patients after HSCT remains the most important cause of death before transplant-related toxicities. Moreover, since only about 40 to 70% (depending on the ethnic context) of patients with high-risk hematological malignancies, eligible for allogeneic HSCT, have a fully HLA-matched sibling or matched unrelated donor (MUD), a great deal of effort has been invested to make the use of an alternative haploidentical sibling donor feasible. The advantage of this procedure is the immediate availability of a donor for almost all patients. <p>The aim of the work described in this thesis has been to implement a strategy to transplant a patient using a HLA haploidentical donor. The strategy is to try to improve DFS that could be applied both in the autologous or allogeneic context: first, by using nonspecific immune manipulation post transplant and then, by developing specific strategies directed against leukemia antigens. Particularly in the allogeneic situation, the aim was to increase the GVL effect without inducing or aggravating the deleterious GVHD. The first part of this thesis described our own clinical results, consisting of three consecutive phase I/II studies, in which we tried to determine the feasibility of giving prophylactic donor lymphocyte infusions (DLI) post transplant and the effect of replacing granulocyte colony-stimulating factor (G-CSF), typically used to speed up neutrophil recovery, with granulocyte macrophage colony-stimulating factor (GM-CSF), which is known for its immunomodulatory properties. The slow immune reconstitution in haploidentical transplant is chiefly responsible for the high incidence of early lethal viral and fungal infections, and most probably for early relapses; therefore, we sought to accelerate and strengthen the post transplant immune reconstitution without increasing the GVHD rate. Thus, we have studied the impact of post transplant growth factor administration and of unselected DLI in haploidentical transplant. We have also implemented, in our center, anti-cytomegalovirus (CMV) specific T cell generation and infusion to improve anti-CMV immune reconstitution. Since then, our results have been pooled in a multi-center analysis performed by the European Bone Marrow Transplantation group (EBMT) allowing us to compare our results with those of the entire group. We have also participated in the design of an ongoing study aimed at selectively depleting the graft from alloreactive T cells, and improving post transplant T cell add-backs. In our attempts to generate and expand ex vivo lymphocytes (directed against pathogens (CMV) and leukemia-associated antigens, Wilms' tumor gene 1 (WT1) and to use them in vivo, we found inconsistent results (in the case of WT1) using classical clinical grade dendritic cells (DC) generated and matured in bags, as was the case for the majority of the teams worldwide. This led us to question the full functionality of these DC and we undertook a thorough comparative analysis of DC generated and differentiated in bags and in plates (typical for most pre-clinical studies). This analysis showed us that one cannot transpose pre-clinical studies (using culture plates) directly to clinical protocols (generally using clinical grade culture bags) and that DC generated in bags are functionally deficient. We learned that, if we want to use a DC vaccine to improve the GVL effect in haploidentical transplant, we will have to be careful about the technique by which they are generated. To improve immunotherapeutic approaches, the understanding of the mechanisms underlying tumor tolerance and how to manipulate them is critical in the development of new effective immunotherapeutic clinical trials. This is why we currently focus on how to obtain effective in vivo anti-leukemia immune reactions using an ex-vivo manipulated product to trigger the immunotherapeutic response. More specifically, we are analyzing the impact of regulatory T cell (Tregs) depletion and function for an adequate anti-leukemic immune response. This pre-clinical work aims at improving the outcome of leukemia patients who have relapsed and been put back into second remission and at decreasing the RR after HSCT, especially in the field of haploidentical transplantation. <p>In conclusion, haploidentical transplantation has become a valuable tool. The results are at least similar to those obtained using MUD when performed in the same group of patients. Specific immunomodulation post transplant can affect events such as GVHD and GVL, but clinically we are still at the level of nonspecific manipulations. It is our hope that ongoing pre-clinical work will enable us to perform specific anti-pathogen and anti-leukemia immune manipulation that will favorably influence the patient outcome.<p>/<p><p>Dans la majorité des situations, le système immunitaire autologue est incapable d’éradiquer les cellules leucémiques résiduelles qui échappent à la radiothérapie et à la chimiothérapie, cependant un équilibre peut s’établir entre les cellules leucémiques et immunitaires aboutissant à une rémission pouvant durer plusieurs mois ou années. Si cet équilibre se rompt, une rechute clinique peut se déclarer. Dans ce contexte, il est prouvé que la greffe allogénique de cellules souches hématopoïétiques est le moyen le plus efficace de renforcer les réactions immunitaires contre la leucémie par la réaction du greffon contre la leucémie et ainsi d’obtenir une éradication définitive de la maladie résiduelle chez un nombre significatif de patients. En effet, le concept global de l’allogreffe de cellules souches hématopoïétiques a évolué du concept de transplantation d’organe (remplacement d’un organe malade par un nouvel organe sain) vers celui de créer une extraordinaire plateforme d’immunothérapie à travers laquelle le système immunitaire du donneur contribue à l’éradication des cellules leucémiques persistantes. Donc, la problématique reste celle de trouver les meilleures modalités d’immunomodulation pour achever une prise du greffon, un effet anti-leucémique puissant du greffon, et l’absence ou un minimum d’effet du greffon contre l’hôte. Différentes stratégies existent pour atteindre cet objectif, comme l’utilisation de cytokines pour moduler la reconstitution immunitaire, des déplétions cellulaires globales ou spécifiques du greffon et l’infusion de cellules immunes «globales» ou spécifiques du donneur après greffe. Ces stratégies sont encore largement à l’étude. Néanmoins, la persistance d’un taux de rechute élevé observé chez les patients leucémiques, après allogreffe reste la cause principale de décès, avant celle liée à la toxicité de la greffe. De plus, étant donné que seulement environ 40 à 70% (dépendant de l’origine ethnique) des patients avec une hémopathie à haut risque, éligibles pour une greffe allogénique, ont un donneur familial ou non familial complètement HLA compatible, des efforts importants ont été développés pour rendre faisable l’utilisation de donneurs familiaux alternatifs, haploidentiques. L’avantage de cette approche est l’accès immédiat à un donneur pour quasiment tous les patients.<p>Le but du travail décrit dans cette thèse a été l’implémentation d’une stratégie d’allogreffe utilisant un donneur haploidentique. Le travail vise également à développer de façon plus large des stratégies qui peuvent améliorer le taux de survie sans rechute, non seulement dans le contexte des greffes haploidentiques, mais également dans le cadre des greffes allogéniques en général, ainsi que dans les situations autologues :premièrement, par la manipulation immunitaire non spécifique après greffe et ensuite par le développement de stratégies spécifiques dirigées contre des antigènes leucémiques. En particulier dans la situation allogénique, le but a été d’augmenter l’effet du greffon contre la leucémie sans induire ou aggraver l’effet délétère du greffon contre l’hôte. La première partie de la thèse décrit les résultats cliniques de notre propre protocole de greffe haploidentique, qui a consisté en trois études consécutives de phase I/II. Dans ces études, nous avons voulu déterminer la faisabilité de réaliser des infusions prophylactiques de lymphocytes du donneur après transplantation, et l’impact du remplacement du « granulocyte colony-stimulating factor » (G-CSF), largement utilisé pour permettre une récupération en polynucléaires neutrophiles plus rapide, par du « granulocyte-macrophage colony-stimulating factor » (GM-CSF), lequel est connu pour ses propriétés immunomodulatrices différentes. La reconstitution immunitaire très lente après greffe haploidentique est majoritairement responsable de l’incidence élevée de décès par infections virales et fungiques précoces, et très probablement des rechutes précoces. C’est pourquoi nous avons cherché à accélérer et à renforcer la reconstitution immunitaire post-greffe sans augmenter la fréquence de réaction du greffon contre l’hôte. Nous avons donc étudié l’impact de l’administration de facteurs de croissance et l’infusion de lymphocytes non sélectionnés du donneur en post greffe haploidentique. Nous avons également implémenté dans notre centre, la génération et l’infusion de lymphocytes T spécifiques anti-cytomégalovirus (CMV) afin d’améliorer la reconstitution immunitaire anti-CMV. D’autre part, nos résultats ont été regroupés dans une étude multicentrique menée par le groupe européen de transplantation de moelle osseuse (EBMT), ce qui nous a permis de comparer nos résultats avec ceux de l’entièreté du groupe. Nous avons parallèlement participé à la conception d’une étude actuellement en cours ayant pour but d’améliorer la reconstitution immunitaire après greffe par la déplétion sélective du greffon en lymphocytes T alloréactifs et par l’infusion après greffe de lymphocytes T du donneur également sélectivement déplétés en lymphocytes T alloréactifs. Afin d’optimaliser l’effet anti-leucémique du système immunitaire, nous avons débuté un protocole de vaccination par cellules dendritiques (DCs). Ces cellules dendritiques étaient chargées en lysat de blastes leucémiques dans le cas de patients présentant au diagnostic une leucémie aigue surexprimant l’oncogène 1 de la tumeur de Wilms (WT1). Néanmoins dans nos travaux de génération et d’expansion ex-vivo de lymphocytes T spécifiques de l’antigène WT1, utilisant les DCs de grade clinique, générées et maturées en poches, nous avons rencontré des résultats inconsistants, comme c’était le cas dans la majorité des protocoles cliniques internationaux de vaccination. Nous nous sommes alors posé la question de la fonctionnalité globale de ces cellules et nous avons entrepris une analyse comparative poussée des DCs générées et différenciées en poches ou en plaques. Les DCs générées en plaques sont celles utilisées dans la plupart des travaux précliniques. Cette analyse nous a montré que l’on ne pouvait pas directement transposer les résultats précliniques basés sur des DCs générées en plaques dans des protocoles cliniques basés sur des DCs générées en poches, car ces dernières présentent des déficits fonctionnels importants. Nous avons appris que si l’on voulait utiliser un vaccin à base de cellules dendritiques pour améliorer l’effet du greffon contre la leucémie dans les greffes allogéniques, nous devions être très attentifs quant au protocole utilisé pour la génération de ces vaccins cellulaires. Pour améliorer les approches immunothérapeutiques, la connaissance des mécanismes qui établissent la tolérance tumorale et des façons de manipuler ceux-ci, est critique dans le développement de nouveaux protocoles efficaces. C’est pourquoi nous nous concentrons actuellement sur les conditions nécessaires à l’obtention in vivo d’une réaction immune anti-leucémique efficace lors de l’utilisation d’un produit cellulaire manipulé ex vivo. Plus spécifiquement, nous analysons l’impact de la déplétion en lymphocytes T régulateurs (Tregs) sur la réponse anti-leucémique. Ce travail préclinique a pour but d’améliorer le devenir de patients leucémiques qui ont rechutés et ont été mis en seconde rémission, ainsi que de diminuer le taux de rechute après allogreffe, spécifiquement après greffe haploidentique. <p>En conclusion, la transplantation haploidentique est actuellement un outil précieux pour de nombreux patients. Les résultats sont au minimum similaires à ceux qui sont obtenus par les greffes non-familiales HLA identiques lorsqu’elles sont pratiquées dans les mêmes groupes de patients. L’immunomodulation spécifique après greffe peut affecter des événements comme la réaction du greffon contre l’hôte et la réaction du greffon contre la leucémie, mais en pratique clinique nous en sommes encore au niveau de la manipulation aspécifique. Nous espérons que les travaux précliniques actuels vont nous permettre d’appliquer des stratégies spécifiques et d’obtenir une manipulation immune anti-leucémique qui aura une influence favorable significative sur le devenir des patients. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Background: The CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemia is a promising treatment for relapsed or refractory malignities. The overall response rate of CD19 CAR-T cells in clinical trials was greater than 80% for patients with B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin's lymphoma (NHL). However, CAR-T cell therapy of leukemias and solid tumors has been limited by a lot of factors such as antigen loss of tumor escape variants, reduced proliferation, persistence and tumor-infiltration of CAR-T cells in vivo, immunosuppressive tumor environment, absence of ideal antigens and on-target, off-tumor toxicities. Therefore, new strategies improving the safety and efficacy of CAR-T cells, including further T-cell modification to overcome the immune suppression, are tested. Aims: (i) Bispecific CARs designed to express two antigen-binding domains prevent of antigen escape. (ii) T-cells were genetically modified to express CAR along with an inducible IL-21 gene cassette driven by NFAT-responsive promoter. IL-21 directly enhances CAR-T cell activity and anti-tumor effects. (iii) Applying suicide epitope modification in CAR enables significantly increasing the therapeutic safety of CAR-T cells. Methods: CARs were constructed by using molecular biology...