Orientadores: Ester Maria Danielli Nicola, Eulália Sakano / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T13:39:38Z (GMT). No. of bitstreams: 1 Ortiz_Erica_D.pdf: 2854168 bytes, checksum: c4f7e3d14049e592b11a3b339481fa12 (MD5) Previous issue date: 2014 / Resumo: Introdução: Acredita-se que a imunossupressão seja única causa para maior prevalência de rinossinusites (RS) no transplantado de células tronco hematopoiéticas (TCTH) principalmente naqueles com Doença do Enxerto contra o Hospedeiro (DECH) crônica. Pacientes submetidos ao TCTH podem apresentar alterações nasossinusais, que podem se relacionar ao próprio transplante, assim como pelo regime de condicionamento ou pela DECH. Entretanto, estas alterações nasossinusais não estão bem descritas na literatura assim como a associação entre estas e a rinossinusite. Objetivo: verificar a histologia e ultraestrutura da mucosa nasossinusal com RS no TCTH com e sem DECH; e verificar a influencia da RS nas possíveis alterações histológicas nestes pacientes. Método: estudo prospectivo exploratório de coorte transversal com análise estatística de dados obtidos da avaliação de mucosa de processo unciforme de pacientes transplantados com (16) e sem DECH (8) com RS; através da microscopia eletrônica de transmissão e óptica. Comparação da recorrência das RS e alterações histológicas. Resultados: 47% (14) tiveram apenas 1 ou 2 episódios e 33%, mais de 3 episódios de rinossinusite. Apenas a presença de microvilosidades foi significativamente maior nos pacientes sem GVHD (p=0,05). Não houve diferença significativa na quantidade de cílios, ultraestrutura ciliar, metaplasia escamosa, células caliciformes, vacuolização citoplasmática, densidade do infiltrado inflamatório, linfócitos, eosinófilos e corpúsculos apoptóticos intraepiteliais, glândulas mucosas, espessura da membrana basal, edema e fibrose subepiteliais entre os grupos com e sem DECH. Houve diminuição significante de cílios conforme maior recorrência de rinossinusite (p=0,008). Conclusão: pacientes com RS e TCTH não apresentaram diferenças nas alterações histológicas nasossinusais, exceto aumento de microvilosidades naqueles sem a DECH. Os transplantados com e sem DECH apresentaram somente diminuição dos cílios conforme o aumento da recorrência de RS / Abstract: INTRODUCTION: It is believed that immunosuppression is the sole cause for the occurrence of rhinosinusitis in hematopoietic stem cell transplant (HSCT). There is a high incidence of sinusitis in recipient patients, especially in those with Chronic Graft-Versus-Host disease (GVHD). Histopathological abnormalities were described in recipients¿ sinus mucosa compared to immunocompetent patients. There were also mucosal abnormalities related to cytotoxicity in the transplanted patients with chronic GVHD but no difference in ultrastructure between HSCT patients with and without GVHD, except for increased goblet cells in patients without GVHD. The relation between the sinonasal mucosa abnormalities of patients with and without GVHD and rhinosinusitis is not well established yet. OBJECTIVE: To verify the ultrastructure of the sinonasal mucosa of HSCT with and without GVHD with rhinosinusitis to understand the cause of high sinusitis incidence in recipients with and without GVHD. METHOD: A prospective study with preliminary exploratory statistical analysis of data obtained from the evaluation of the uncinate process mucosa of patients transplanted with (16) and without GVHD (8) with rhinosinusitis by transmission electron and optical microscopy. RESULTS: Of the patients, 47% (14) had only 1 or 2 episodes, and 33% had more than 3 episodes of rhinosinusitis. Only the presence of microvilli was significantly higher in patients without GVHD. There was no significant difference in the amount of cilia, ciliary ultrastructure, squamous metaplasia, goblet cells, vacuolization, density of the inflammatory infiltrate, intraepithelial lymphocytes, eosinophils, mucous glands, apoptotic corpuscles intraepithelial basement membrane thickness, edema and subepithelial fibrosis between groups. There was a significant decrease of cilia with higher recurrence of rhinosinusitis. CONCLUSION: There was an increase in microvilli HSCT without GVHD with rhinosinusitis, and the ultrastructure and histological changes of HSCT with and without GVHD did not change with the recurrence of rhinosinusitis. However, there was a decrease of cilia in the epithelium of the sinonasal HSCT with higher recurrence of rhinosinusitis / Doutorado / Otorrinolaringologia / Doutora em Ciências Médicas

A esclerose múltipla (EM) é uma doença desmielinizante inflamatória crônica recorrente, restrita ao sistema nervoso central (SNC), cuja característica histológica é a ocorrência de desmielinização relacionada com infiltrado inflamatório perivenular com relativa preservação axonal. A forma clássica da doença se caracteriza pela recorrência de ataques (surtos), seguidos de remissão dos sintomas (RRMS), com a presença de múltiplas lesões focais dispersas pelo SNC (dissociação espacial) com processo inflamatório exuberante na fase aguda, coexistindo com lesões crônicas (dissociação temporal) sem atividade inflamatória evidenciavel pela quebra de barreira hematoencefálica e realce na fase contrastada na imagem de ressonância magnética (MRI). Alguns pacientes tem uma evolução benigna, permanecendo livre de sequelas significativas por mais de 20 anos da doença. Outros pacientes têm uma forma agressiva da doença, ficando restritos à cadeira de rodas em 8 a 10 anos de evolução. Um desafio é modificar o curso desta forma agressiva, o que pode ser feito com o uso de imunomoduladores, quimioterápicos e, eventualmente, transplante autólogo de células tronco hematopoiéticas (aHSCT). O objetivo da utilização do aHSCT é a restauração da atividade imunológica livre dos ataques à mielina (\"autoimune reset\"). Uma das maneiras de se monitorar a eficácia do tratamento é a identificação da ocorrência de novas lesões e de lesões com reforço visíveis em exames de RM seriados. Objetivo: Testar a hipótese de que o tratamento de pacientes com EM, utilizando AHSCT, foi eficaz em evitar a recorrência de inflamação e o aparecimento de novas lesões visíveis na SB ao exame de MRI, a longo prazo. Resultados: Na nossa Instituição, cerca de 66 pacientes portadores de EM foram tratados com aHSCT no período de 2004 a 2011, sendo seguidos desde então pelas disciplinas de hematologia, neurologia/neuroimunologia e pela seção de RM do CCIFM-HCRP. Método: Foram revisados os exames de RM de encéfalo adquiridos de maneira prospectiva e protocolada, de 76 pacientes submetidos ao aHSCT, com seguimento por MRI há mais de cinco anos. As imagens de RM foram arquivadas nos servidores do CCIFM, foram recuperadas, anonimizadas e revistas por pelo menos dois radiologistas experientes, de maneira independente e por confrontação. Foi considerada falha terapêutica a identificação de lesões novas e/ou lesões com reativação inflamatória. Resultados: Dez pacientes foram excluídos. Doze pacientes (18,18%) apresentaram novas lesões ou recorrência do processo inflamatório, com reforço. Conclusão: Na nossa amostra o aHSCT foi capaz de controlar a recorrência de lesões e da atividade inflamatória perceptível na RM em mais de 87% dos casos, caracterizando uma importante opção terapêutica de segunda linha nos casos de maior agressividade da doença / Multiple sclerosis (MS) is a recurrent chronic inflammatory demyelinating disease, restricted to the central nervous system (CNS), whose histological feature is the occurrence of perivenular inflammatory infiltrate, leading to demyelination with relative axonal preservation. The classic form of the disease is characterized by the recurrence of attacks (outbreaks), followed by remission of symptoms (RRMS), with the presence of multiple focal lesions dispersed by the CNS (spatial dissociation) with exuberant inflammatory process in the acute phase, coexisting with chronic lesions (Temporal dissociation) without inflammatory activity evidenced by the breakdown of blood-brain barrier and contrast-enhanced contrast-enhanced magnetic resonance imaging (MRI). Some patients have a benign course, remaining free of significant sequelae for more than 20 years of the disease. Other patients have an aggressive form of the disease, being restricted to the wheelchair in 8 to 10 years of evolution. One challenge is to modify the course in this aggressive way, which can be done with the use of immunomodulators, chemotherapeutics and, eventually, autologous hematopoietic stem cell transplantation (aHSCT). The goal of using aHSCT is to restore immune activity free of myelin attacks (\"autoimmune reset\"). One of the ways to monitor treatment efficacy is to identify the occurrence of new lesions and visible reinforcing lesions on serial MRI scans. Objective: To test the hypothesis that the treatment of patients with MS using AHSCT was effective in avoiding the recurrence of inflammation and the appearance of new visible lesions in SB at the long-term examination of MRI. Results: At our institution, approximately 66 patients with MS were treated with aHSCT from 2004 to 2011, followed by the hematology, neurology / neuroimmunology and MRI sections of the CCIFM-HCRP. Methods: Brain and MRI scans acquired in a prospective and protocolized way from 76 patients who underwent aHSCT were followed up with MRI for more than five years. The MR images were archived on the CCIFM servers, retrieved, anonymised and reviewed by at least two experienced radiologists, independently and by confrontation. The identification of new lesions and / or lesions with inflammatory reactivation was considered therapeutic failure. Results: Ten patients were excluded. Twelve patients (18.18%) presented new lesions or recurrence of the inflammatory process, with reinforcement. Conclusion: In our sample, aHSCT was able to control the recurrence of lesions and the inflammatory activity detected in MRI in more than 87% of the cases, characterizing an important second line therapeutic option in the cases of greater aggressiveness of the disease.

A esclerose múltipla (EM) é uma doença desmielinizante inflamatória crônica recorrente, restrita ao sistema nervoso central (SNC), cuja característica histológica é a ocorrência de desmielinização relacionada com infiltrado inflamatório perivenular com relativa preservação axonal. A forma clássica da doença se caracteriza pela recorrência de ataques (surtos), seguidos de remissão dos sintomas (RRMS), com a presença de múltiplas lesões focais dispersas pelo SNC (dissociação espacial) com processo inflamatório exuberante na fase aguda, coexistindo com lesões crônicas (dissociação temporal) sem atividade inflamatória evidenciavel pela quebra de barreira hematoencefálica e realce na fase contrastada na imagem de ressonância magnética (MRI). Alguns pacientes tem uma evolução benigna, permanecendo livre de sequelas significativas por mais de 20 anos da doença. Outros pacientes têm uma forma agressiva da doença, ficando restritos à cadeira de rodas em 8 a 10 anos de evolução. Um desafio é modificar o curso desta forma agressiva, o que pode ser feito com o uso de imunomoduladores, quimioterápicos e, eventualmente, transplante autólogo de células tronco hematopoiéticas (aHSCT). O objetivo da utilização do aHSCT é a restauração da atividade imunológica livre dos ataques à mielina (\"autoimune reset\"). Uma das maneiras de se monitorar a eficácia do tratamento é a identificação da ocorrência de novas lesões e de lesões com reforço visíveis em exames de RM seriados. Objetivo: Testar a hipótese de que o tratamento de pacientes com EM, utilizando AHSCT, foi eficaz em evitar a recorrência de inflamação e o aparecimento de novas lesões visíveis na SB ao exame de MRI, a longo prazo. Resultados: Na nossa Instituição, cerca de 66 pacientes portadores de EM foram tratados com aHSCT no período de 2004 a 2011, sendo seguidos desde então pelas disciplinas de hematologia, neurologia/neuroimunologia e pela seção de RM do CCIFM-HCRP. Método: Foram revisados os exames de RM de encéfalo adquiridos de maneira prospectiva e protocolada, de 76 pacientes submetidos ao aHSCT, com seguimento por MRI há mais de cinco anos. As imagens de RM foram arquivadas nos servidores do CCIFM, foram recuperadas, anonimizadas e revistas por pelo menos dois radiologistas experientes, de maneira independente e por confrontação. Foi considerada falha terapêutica a identificação de lesões novas e/ou lesões com reativação inflamatória. Resultados: Dez pacientes foram excluídos. Doze pacientes (18,18%) apresentaram novas lesões ou recorrência do processo inflamatório, com reforço. Conclusão: Na nossa amostra o aHSCT foi capaz de controlar a recorrência de lesões e da atividade inflamatória perceptível na RM em mais de 87% dos casos, caracterizando uma importante opção terapêutica de segunda linha nos casos de maior agressividade da doença / Multiple sclerosis (MS) is a recurrent chronic inflammatory demyelinating disease, restricted to the central nervous system (CNS), whose histological feature is the occurrence of perivenular inflammatory infiltrate, leading to demyelination with relative axonal preservation. The classic form of the disease is characterized by the recurrence of attacks (outbreaks), followed by remission of symptoms (RRMS), with the presence of multiple focal lesions dispersed by the CNS (spatial dissociation) with exuberant inflammatory process in the acute phase, coexisting with chronic lesions (Temporal dissociation) without inflammatory activity evidenced by the breakdown of blood-brain barrier and contrast-enhanced contrast-enhanced magnetic resonance imaging (MRI). Some patients have a benign course, remaining free of significant sequelae for more than 20 years of the disease. Other patients have an aggressive form of the disease, being restricted to the wheelchair in 8 to 10 years of evolution. One challenge is to modify the course in this aggressive way, which can be done with the use of immunomodulators, chemotherapeutics and, eventually, autologous hematopoietic stem cell transplantation (aHSCT). The goal of using aHSCT is to restore immune activity free of myelin attacks (\"autoimmune reset\"). One of the ways to monitor treatment efficacy is to identify the occurrence of new lesions and visible reinforcing lesions on serial MRI scans. Objective: To test the hypothesis that the treatment of patients with MS using AHSCT was effective in avoiding the recurrence of inflammation and the appearance of new visible lesions in SB at the long-term examination of MRI. Results: At our institution, approximately 66 patients with MS were treated with aHSCT from 2004 to 2011, followed by the hematology, neurology / neuroimmunology and MRI sections of the CCIFM-HCRP. Methods: Brain and MRI scans acquired in a prospective and protocolized way from 76 patients who underwent aHSCT were followed up with MRI for more than five years. The MR images were archived on the CCIFM servers, retrieved, anonymised and reviewed by at least two experienced radiologists, independently and by confrontation. The identification of new lesions and / or lesions with inflammatory reactivation was considered therapeutic failure. Results: Ten patients were excluded. Twelve patients (18.18%) presented new lesions or recurrence of the inflammatory process, with reinforcement. Conclusion: In our sample, aHSCT was able to control the recurrence of lesions and the inflammatory activity detected in MRI in more than 87% of the cases, characterizing an important second line therapeutic option in the cases of greater aggressiveness of the disease.

No description available.

La greffe de cellules souches hématopoïétiques (CSH) constitue une avancée thérapeutique considérable dans le traitement de maladies hématologiques et non hématologiques. Toutefois, malgré qu’elle sauve des vies, elle n’est pas sans risque. Le syndrome lymphoprolifératif post-transplantation (SLPT) est l’une des complications qui peut survenir après ce type de greffe avec un risque de mortalité pouvant atteindre 80% en l’absence de traitement. Par ailleurs, les traitements disponibles pour limiter le développement de ce syndrome ne sont pas sans effets néfastes. Le SLPT est surtout une conséquence d’une primo-infection ou d’une réactivation non-contrôlée du virus d’Epstein-Barr (VEB). Au moins 90% des adultes sont porteurs du VEB alors que ce pourcentage est d’environ 50-70% chez les enfants. Il est important de bien comprendre les facteurs de risque de l’infection active du VEB et du SLPT pour une meilleure gestion des greffés. Cette thèse a pour objectif de contribuer aux connaissances quant aux déterminants du VEB et du SLPT chez les greffés pédiatriques de CSH. Dans un premier temps, une revue systématique combinée à une méta-analyse a été réalisée pour élaborer un portrait exhaustif des facteurs de risque connus du VEB et du SLPT chez les greffés adultes et pédiatriques de CSH. Ensuite, à l’aide d’une étude de cohorte prospective multicentrique canadienne qui a enrôlé 156 patients pédiatriques greffés de CSH, le lien entre la transfusion de produits sanguins et l’infection VEB post-greffe a été analysé. Finalement, l’étude de cohorte multicentrique a aussi permis d’explorer des nouveaux facteurs de risque des évènements liés au VEB allant de l’ADNémie VEB à la suspicion du SLPT. Les résultats de la revue systématique et de la méta-analyse ont montré que l’utilisation de la globuline antithymocyte (ATG) pour prévenir la maladie du greffon contre l’hôte est le principal facteur impliqué dans la survenue post-greffe des infections actives du VEB et du SLPT. La forte hétérogénéité entre les études a limité la comparaison des résultats et très peu d’études portaient exclusivement sur les patients pédiatriques. D’autre part, l’analyse statistique au sein de la cohorte multicentrique n’a pas révélé une augmentation statistiquement significative du risque d’infection du VEB post-greffe associé à la transfusion. Toutefois, une analyse de génotypage du virus a indiqué que la transfusion serait très probablement liée à la primo-infection VEB d’un patient séronégatif, et ce malgré la leucoréduction (qui élimine virtuellement la présence des virus associés aux composantes cellulaires des produits sanguins). Par ailleurs, nos analyses dans la cohorte multicentrique ont corroboré l’association entre l’ATG et les évènements liés au VEB post-greffe et mis en relief deux nouvelles associations. Le mycophénolate mofétil, un médicament utilisé pour prévenir la maladie du greffon contre l’hôte, limiterait le risque des évènements liés au VEB par son action antiproliférative des lymphocytes T et B (incluant ceux infectés par le VEB), tandis que les filles seraient plus à risque des formes relativement sévères de l’infection du VEB post-greffe que les garçons. Le rationnel autour de cette dernière association n’est pas connu. Des nouvelles recherches permettront d’apprécier la reproductibilité de ces résultats. / Hematopoietic stem cell transplantation (HSC) constitutes a notable therapeutic advance in the treatment of hematological and non-hematological diseases. However, despite saving lives, it is not without risk. Post-transplant lymphoproliferative disease (PTLD) is one of the complications that can occur after this type of transplant with a mortality risk of up to 80% if left untreated. Moreover, the treatments available to limit the development of this disease are not without harmful effects on transplant recipients. PTLD is predominantly a consequence of primary infection or uncontrolled reactivation of Epstein-Barr virus (EBV). At least 90% of adults are carriers of EBV, compared to around 50-70% in the pediatric population. It is important to understand the risk factors for active EBV infection and PLTD in order to better manage transplant recipients. This thesis aims to contribute to knowledge on the determinants of active EBV infection and PTLD in pediatric HSC transplant recipients. A systematic review combined with a meta-analysis was carried out to develop a comprehensive portrait of the known risk factors for EBV and PTLD in adult and pediatric HSC transplant recipients. Then, using a Canadian multicenter prospective cohort study that enrolled 156 pediatric HSC transplant patients, the link between blood product transfusion and post-transplant EBV infection was analyzed. Finally, the multicenter cohort study also explored new risk factors for EBV-related events ranging from EBV DNAemia to suspicion of PTLD. The results of the systematic review and the meta-analysis revealed that the use of anti-thymocyte globulin (ATG) to prevent graft-versus-host disease is the main factor implicated in the post-transplant occurrence of active EBV infection and PTLD. The high heterogeneity between studies limited the comparison of results and very few studies focused exclusively on pediatric patients. On the other hand, statistical analysis within the multicenter cohort did not reveal a significant increase in the risk of post-transplant EBV infection associated with transfusion. However, genotyping analysis of viral strains from blood donors of an EBV-negative patient who received an EBV-negative graft indicated that one of the blood donors was the source of the primary EBV infection in the patient, despite leukoreduction (which virtually eliminates the presence of cell-associated viruses in blood products). Furthermore, our analyses in the multicenter cohort corroborated the association between ATG and post-transplant EBV-related events, and highlighted two new associations. First, mycophenolate mofetil, a drug used to prevent graft-versus-host disease, is believed to reduce the risk of EBV-related events through its antiproliferative action on T and B lymphocytes (including EBV-infected B cells). Second, girls are more at risk of relatively severe forms of post-transplant EBV infection than boys. The rationale behind this latter association is unknown. New research will make it possible to assess the reproducibility of these results.

Malgré les progrès en matière de greffe de cellules souches hématopoïétique (GCSH), environ 40% des enfants atteints d’une leucémie aigüe lymphoblastique (LAL) réfractaire à la chimiothérapie ne peuvent être guéris. Notre laboratoire a démontré que l’effet précoce de greffe contre leucémie (GvL) est significativement augmenté par les cellules Natural Killer (NK) stimulées par des cellules plasmacytoïdes dendritiques (pDC). Une nouvelle thérapie cellulaire adoptive basée sur la stimulation des cellules NK par les pDC a été développée et son efficacité a été démontrée dans un modèle de souris humanisées. Des cellules hautement spécialisées appelées « Therapeutic Inducers of Natural Killer cell Killing » (ThINKK), analogues des pDC, sont produites à partir de cellules souches hématopoïétiques de sang de cordon. Afin d’amener les ThINKK vers un usage clinique, ce projet avait comme objectif d’en compléter la caractérisation, d’investiguer leurs effets secondaires potentiels après transfert adoptif dans le contexte de transplantation hématopoïétique allogénique et d’évaluer l’impact d’un régime prophylactique immunosuppresseur sur l’axe ThINKK/cellules NK. L’identité cellulaire des ThINKK a été déterminée par cytométrie de flux et par analyse unicellulaire du transcriptome (scRNA-seq). Pour déterminer si la présence des ThINKK pourrait augmenter l’activation et la prolifération des cellules T allogéniques, nous avons utilisé des réactions lymphocytaires mixtes (MLR) dans lesquelles les cellules T et les ThINKK ont été cultivées en présence de cellules présentatrices d’antigènes. Un modèle murin de réaction de greffe contre l’hôte (xéno-GvHD) nous a permis de déterminer l’impact du transfert adoptif de ThINKK sur la GvHD in vivo. Finalement, nous avons testé l’effet d’immunosuppresseurs sur la cytotoxicité des cellules NK activées par ThINKK contre des cellules LAL. Nos résultats démontrent que les ThINKK n’expriment pas les marqueurs associés aux cellules présentatrices d’antigènes, mais expriment les marqueurs des cellules plasmacytoïdes dendritiques. L’analyse des résultats de scRNA-seq démontre la présence d’une sous-population cellulaire mineure exprimant le récepteur AXL, sans toutefois exprimer les autres marqueurs conventionnels des cellules présentatrices d’antigènes. Les ThINKK, incluant la sous-population AXL-positive, n’exacerbent pas l’activation ou la prolifération des cellules T allogéniques in vitro ou in vivo. Finalement, des cinq immunosuppresseurs testés, seules la cyclosporine A et de la méthylprednisolone diminuaient l’activation et la cytotoxicité des cellules NK induites par les ThINKK. Nos résultats suggèrent qu’une immunothérapie par transfert adoptif de ThINKK serait sécuritaire chez les patients ayant reçu une greffe allogénique. L’utilisation d’un régime prophylactique immunosuppresseur est également possible sans affecter l’efficacité de cette nouvelle immunothérapie post-transplantation. / The survival outcomes of children with relapsed acute lymphoblastic leukemia (ALL) remain dismal despite progress in hematopoietic stem cell transplantation. In the past, our team has demonstrated that the stimulation of Natural Killer (NK) cells with a subset of plasmacitoid dendritic cells (pDCs) called Therapeutic Inducers of Natural Killer cell Killing (ThINKK) improved the early graft-versus-leukemia effect and controlled ALL development in humanized mice. ThINKK are expanded from cord blood hematopoietic stem cell progenitors for adoptive post-transplant immunotherapy. To translate these findings into the clinic, the main objectives of this project was to further characterize the ThINKK phenotype, to investigate the potential adverse effects of ThINKK in the context of allogeneic hematopoietic transplantation, and to evaluate the functional impact of the post-transplant prophylactic immunosuppressive regimen on the ThINKK/NK cell axis. The cellular identity of ThINKK was assessed using flow cytometry and single-cell RNA sequencing. To assess the potential exacerbation of T-cell activation and proliferation by ThINKK, allogeneic T cells and ThINKK were co-cultured with or without antigen-presenting cells in mixed lymphocyte reactions (MLR). We used a xenograft mouse model to evaluate the efficacy and potential side effects of an adoptive transfer of ThINKK on graft-versus-host reactions in vivo. Finally, we tested the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells. We found that ThINKK cells did not express antigen-presenting cell markers but expressed pDCs lineage markers. Single-cell RNA sequencing analysis revealed the presence of a minor cell subset expressing the AXL receptor gene, but lacking expression of other conventional dendritic cell marker genes. Importantly, ThINKK including the AXL+ subset did not exacerbate allogeneic T-cell activation and proliferation in vitro and in vivo. Finally, out of the five immunosuppressive drugs tested, only cyclosporine A and methylprednisolone decreased ThINKK-induced NK cell activation and cytotoxicity. Our results support that ThINKK cell transfer immunotherapy could be safe in transplanted subjects even in allogeneic settings and that a prophylactic immunosuppressive regimen may be used without affecting the efficacy of this novel post-transplant immunotherapy.