PhD / The aims of this study were to test the efficacy of immunoglobulin and its Fab and Fc fragment in the treatment of experimental autoimmune neuritis (EAN) in Lewis rats, to investigate which portion of immunoglobulin is operative in the effect of IVIg, and to clarify the possible mechanisms by which immunoglobulin exerts its action in the treatment of rats EAN. EAN was induced by immunization with whole bovine peripheral nerve myelin. The immunized rats were randomized into groups, assessed clinically, electrophysiologically, and histologically, and intravenously injected with normal saline, albumin, human IVIg preparation, purified Fab or Fc fragments. The treatment efficacy was compared between normal saline and albumin groups, albumin and IVIg groups, albumin and Fab groups, albumin and Fc groups, Fab and Fc groups, Fab and IVIg groups, and Fc and IVIg groups. Methods of myelin isolation, antibody purification, and Western blot techniques were also applied. The results revealed that treatment with Fc fragment and IVIg at the onset of signs of disease effectively prevented further progression of disease, shortened disease duration, and facilitating recovery from illness as shown in clinical, electrophysiological and histological parameters. In the study which the efficacy of albumin and IVIg was compared, 5 out of 17 rats (29%) in the albumin group and 12 out of 17 (71%) in the IVIg group completely recovered from the clinical disease by day 30. The animals receiving IVIg treatment exhibited lower clinical scores, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades. In the study which the efficacy of albumin, Fab fragment, Fc fragment, and IVIg was compared, 0 out of 8 (0%) in the albumin group, 1 out of 8 (13%) in the Fab group, 4 out of 8 (50%) in the Fc group, and 6 out of 9 (67%) rats in the IgG group completely recovered from the clinical disease by day 30. The animals receiving Fc fragment and IVIg treatment exhibited lower clinical scores, less prominent weight loss, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades.

Intravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however, its mechanism of action remains elusive. Our results demonstrate a novel finding wherein IVIg treatment induces a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and that the liver is the organ of increased IL-11 transcription. Furthermore, we show that IL-11Rα knockout mice, although initially protected, become resistant to protection by IVIg during experimental autoimmune encephalomyelitis (EAE) and develop disease with a similar incidence and severity as control-treated IL-11Rα-/- mice. The inability of IVIg to prevent EAE in IL-11Rα-/- mice correlated with a failure of this agent to decrease IL-17 production by myelin-reactive T-cells in the draining lymph nodes. Finally, we show that IL-11 can directly inhibit IL-17 production by lymph node cells in culture. Together, these results implicate IL-11 as an important immune effector of IVIg in the amelioration of EAE.

Intravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however, its mechanism of action remains elusive. Our results demonstrate a novel finding wherein IVIg treatment induces a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and that the liver is the organ of increased IL-11 transcription. Furthermore, we show that IL-11Rα knockout mice, although initially protected, become resistant to protection by IVIg during experimental autoimmune encephalomyelitis (EAE) and develop disease with a similar incidence and severity as control-treated IL-11Rα-/- mice. The inability of IVIg to prevent EAE in IL-11Rα-/- mice correlated with a failure of this agent to decrease IL-17 production by myelin-reactive T-cells in the draining lymph nodes. Finally, we show that IL-11 can directly inhibit IL-17 production by lymph node cells in culture. Together, these results implicate IL-11 as an important immune effector of IVIg in the amelioration of EAE.

PhD / The aims of this study were to test the efficacy of immunoglobulin and its Fab and Fc fragment in the treatment of experimental autoimmune neuritis (EAN) in Lewis rats, to investigate which portion of immunoglobulin is operative in the effect of IVIg, and to clarify the possible mechanisms by which immunoglobulin exerts its action in the treatment of rats EAN. EAN was induced by immunization with whole bovine peripheral nerve myelin. The immunized rats were randomized into groups, assessed clinically, electrophysiologically, and histologically, and intravenously injected with normal saline, albumin, human IVIg preparation, purified Fab or Fc fragments. The treatment efficacy was compared between normal saline and albumin groups, albumin and IVIg groups, albumin and Fab groups, albumin and Fc groups, Fab and Fc groups, Fab and IVIg groups, and Fc and IVIg groups. Methods of myelin isolation, antibody purification, and Western blot techniques were also applied. The results revealed that treatment with Fc fragment and IVIg at the onset of signs of disease effectively prevented further progression of disease, shortened disease duration, and facilitating recovery from illness as shown in clinical, electrophysiological and histological parameters. In the study which the efficacy of albumin and IVIg was compared, 5 out of 17 rats (29%) in the albumin group and 12 out of 17 (71%) in the IVIg group completely recovered from the clinical disease by day 30. The animals receiving IVIg treatment exhibited lower clinical scores, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades. In the study which the efficacy of albumin, Fab fragment, Fc fragment, and IVIg was compared, 0 out of 8 (0%) in the albumin group, 1 out of 8 (13%) in the Fab group, 4 out of 8 (50%) in the Fc group, and 6 out of 9 (67%) rats in the IgG group completely recovered from the clinical disease by day 30. The animals receiving Fc fragment and IVIg treatment exhibited lower clinical scores, less prominent weight loss, less prolongation of S wave latencies, better maintained S wave amplitudes, less reduction of distal motor NCVs, better maintained distal and proximal CMAP amplitudes, and lower histological grades.

Pulmonary embolism (PE) is a common clinical problem affecting 600,000 patients per year in the United States. Although the diagnosis can be easily confirmed by imaging techniques, such as computed tomographic angiography of the chest, the identification of underlying mechanism leading to PE is important for appropriate duration of anticoagulation, and prevention of subsequent episodes. The differential diagnosis of underlying mechanism is broad and must include careful review of medication history. Drug-related thromboembolic disease can be easily missed and may have catastrophic consequences. The identification of the culprit drug is important for prevention of subsequent episodes and choosing appropriate duration of anticoagulation. We report a case of a middle-aged man who developed PE after administration of intravenous immunoglobulin.

Intravenous immunoglobulin (IVIG) is a common treatment for the neurological autoimmune diseases multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy. However, there is scant literature regarding the psychological effects of this treatment on quality of life (QOL). Using illness intrusiveness theory and personal control theory, this correlational, cross-sectional study examined the relationship between the IVIG treatment experience and QOL in neurological autoimmune patients. Surveys were employed to collect data from 79 patients at a neurological infusion center in Phoenix, AZ. Quantitative analyses included correlation, multiple regression, and mediation analyses to determine whether (a) IVIG treatment experience predicted QOL measured by 10 Neuro-QOL scales, (b) illness intrusiveness mediated the relationship between IVIG treatment experience and QOL, and (c) personal control mediated the relationship between illness intrusiveness and QOL. IVIG treatment experience predicted QOL in 1 Neuro-QOL subscale; illness intrusiveness mediated 9 of the Neuro-QOL subscales using bias-corrected bootstrapping for statistical significance; and personal control did not mediate the relationship between illness intrusiveness and QOL. These results may affect social change by increasing the understanding of physicians, nurses, and patients regarding the psychosocial impact of IVIG treatment. Results from the study may provide insight for interventions to assist patients in adjusting to this form of treatment.

Les immunoglobulines circulantes jouent un rôle critique dans l’homéostasie immune en modulant les fonctions des cellules du système immunitaire. Au cours de ma thèse, j’ai exploré les effets régulateurs des immunoglobulines G thérapeutiques (IVIG) et des immunoglobulines A monomériques circulantes (mIgA) sur l’autophagie et les réponses Th17 respectivement. Les IVIg sont une préparation thérapeutique d’IgG normales poolées. Elles ont utilisées comme agent anti-inflammatoire dans le traitement de maladies auto-immunes et inflammatoires variées. Cependant, les mécanismes ne sont pas complètement élucidés et plusieurs mécanismes mutuels et non exclusifs ont été proposés. L’autophagie est un important processus biologique impliquant la dégradation lysosomale des composants cellulaires endommagés et des protéines mal repliées. Il y a plusieurs preuves montrant l’implication de l’autophagie dans les maladies auto-immunes et auto-inflammatoires incluant la découverte de polymorphismes dans des gènes liés à l’autophagie. J’ai montré que l’induction de l’autophagie par les IVIG représente un nouveau mécanisme d’action permettant leur effet thérapeutique dans les maladies auto-immunes et inflammatoires. Les Th17 représentent une cible attractive pour traiter plusieurs maladies inflammatoires et auto-immunes. Malgré le fait qu’elles sont le deuxième anticorps le plus abondant dans la circulation, la function immunorégulatrice des IgA n’est relativement pas explorée. J’ai montré que les IgA monomériques (mIgA) inhibent la différentiation et l’amplification des cellules Th17 humaines et la production de leur cytokine effectrice IL-17A. / Circulating immunoglobulins play a critical role in the immune homeostasis by modulating the functions of immune cells. In my thesis, I investigated the regulatory effects of therapeutic immunoglobulin G (IVIG) and circulating monomeric immunoglobulin A (mIgA) on autophagy and human Th17 response respectively. IVIG is a therapeutic preparation of pooled normal IgG. It is used as an anti-inflammatory agent in the treatment of a wide variety of autoimmune and inflammatory diseases. However, the mechanisms are not yet fully elucidated and several mutually non-exclusive mechanisms have been proposed. Autophagy is an important biological process involving lysosomal degradation of damaged cellular components and misfolded proteins. There are several evidences that support the involvement of autophagy in autoimmune and auto- inflammatory disorders including the discovery of polymorphisms in autophagy-related genes. I show that induction of autophagy by IVIG represents a novel mechanism of action in achieving therapeutic effect in autoimmune and inflammatory diseases. Th17 cells represent an attractive target to treat several inflammatory and autoimmune diseases. Despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. I have shown that monomeric IgA (mIgA) inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第21456号 / 社医博第90号 / 新制||社医||10(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 滝田 順子, 教授 小杉 眞司, 教授 三森 経世 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Objetivo: Comparar as relações de custo-efetividade de duas terapias, Imunoglubulina Intravenosa (IgIV) e Plasmaferese (PE), no tratamento da Síndrome de Guillain-Barré sob a perspectiva do sistema público (SUS). O objetivo secundário foi avaliar a adesão às recomendações da Comissão de Medicamentos do HCPA Métodos: estudo transversal com análise econômica de pacientes tratados por Síndrome de Guillain-Barré no período de junho de 2003 a junho de 2008 no Hospital de Clínicas de Porto Alegre (HCPA). Foi realizada análise de custo-efetividade do emprego de IgIV e de PE nestes pacientes, pelo método de minimização de custos, considerando-se somente os custos diretos sanitários, fornecidos pelo sistema gerencial da instituição . Foram excluídos os pacientes que usaram outro tipo de tratamento associado ou isolado. Coletaram-se os dados através da revisão dos prontuários. A gravidade da doença na internação foi classificada como: doença leve, quando caminhar foi possível; doença moderada, quando caminhar foi impossível; doença grave, quando os pacientes necessitaram de ventilação assistida. A incapacidade na alta foi estabelecida pela escala de sete pontos de Hughes. A adesão às recomendações da Comissão de Medicamentos do HCPA, objetivo secundário, foi avaliada através da dose e o esquema de prescrição da IgIV. Resultados: Vinte e cinco participantes (2 a 70 anos) foram incluídos no estudo, cinco tratados com PE, empregando-se Albumina Humana como substituto do plasma, e 20 tratados com IgIV. O custo total do tratamento de um paciente com PE foi R$10.603,88 (± 2.978,12) e o de um que recebeu IgIV foi R$ 32.103,00 (± 21.454,24). O custo total da internação foi de R$45.027,14 (± 32.750,45) para os tratados com PE e de R$ 60.844,28 (±48.590,52) para os que receberam IgIV. Em relação ao desfecho clínico principal, melhora na escala de incapacidade de sete pontos, após o tratamento com uma das alternativas escolhida, a mediana dos pacientes que internaram com grau de gravidade 3 e que foram tratados com PE foi igual a dos que receberam IgIV. Em relação à permanência hospitalar, permanência em UTI e dias de Ventilação Mecânica, não houve diferença estatisticamente significativa entre os dois tratamentos. Conclusões: Quando comparados os custos médios das duas opções terapêuticas, uma delas aparece claramente com menor custo. Quando comparados os desfechos, após o emprego de cada opção terapêutica, estes não revelam diferença. Concluímos que, no HCPA, a opção pelo procedimento Plasmaferese é mais custo efetiva do que o emprego da IgIV. / Objectives: To compare the cost-effectiveness of two distinct therapies, Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) in the treatment of Guillain-Barré Syndrome, concerning the public health care system. Compliance to the guidelines of the Pharmacy and Therapeutics Committee of the Hospital de Clínicas de Porto Alegre was a secondary objective. Methods: A cross-sectional, economical analysis was conducted, including patients treated for GBS in the period from June, 2003 through June, 2008 in Hospital de Clínicas de Porto Alegre (HCPA). The cost-effectiveness of the use of IVIg and PE in such patients was studied through the cost minimization method, considering direct medical costs only (2008 currency), yield by the management of the institution. Patients receiving treatments other than PE or IVIg were excluded. Data were collected by chart reviews. Severity of disease on admittance was classified as follows: mild disease, when the patient was able to walk; moderate disease, when the patient was unable to walk, and severe disease, when assisted ventilation was required. Disability on discharge was established by the 7-point scale of Hughes. Compliance to the guidelines of the Pharmacy and Therapeutics Committee was evaluated through the dose and prescription scheme of IVIg. Results: Twenty-five participants (2 to 70 years of age) were included in the study, 5 were submitted to treatment with PE, using human albumin as replacement for plasma, and 20 were treated with IVIg. The total treatment cost for PE in a single patient was US$6,058.85 (±1,701.78 SD), and the same expense for IVIg was US$18,344.57 (± 12,259.56 SD) (p = 0.035). Total inpatient cost was US$25,729.79 (± 18,714.54 SD) in the PE group, and US$34,768.16 (±27,766.01 SD) (p=0.530) in the IVIg group. The main clinical outcome was improvement in the 7-point disability grade scale. The median of that measure in patients admitted with a severity grade 3 treated either with PE and IVIg was the same. Secondary outcomes, such as in-hospital stay, ICU stay, and number of days on mechanical ventilation revealed no statistically significant difference between treatments. Conclusions: As the mean expenses of both therapeutic options are compared, one clearly stands-out as less onerous. Clinical outcomes, when compared, reveal no statistical difference after each treatment. We concluded that, in HCPA, plasma exchange is more cost-effective than intravenous immunoglobulin.

Objetivo: Comparar as relações de custo-efetividade de duas terapias, Imunoglubulina Intravenosa (IgIV) e Plasmaferese (PE), no tratamento da Síndrome de Guillain-Barré sob a perspectiva do sistema público (SUS). O objetivo secundário foi avaliar a adesão às recomendações da Comissão de Medicamentos do HCPA Métodos: estudo transversal com análise econômica de pacientes tratados por Síndrome de Guillain-Barré no período de junho de 2003 a junho de 2008 no Hospital de Clínicas de Porto Alegre (HCPA). Foi realizada análise de custo-efetividade do emprego de IgIV e de PE nestes pacientes, pelo método de minimização de custos, considerando-se somente os custos diretos sanitários, fornecidos pelo sistema gerencial da instituição . Foram excluídos os pacientes que usaram outro tipo de tratamento associado ou isolado. Coletaram-se os dados através da revisão dos prontuários. A gravidade da doença na internação foi classificada como: doença leve, quando caminhar foi possível; doença moderada, quando caminhar foi impossível; doença grave, quando os pacientes necessitaram de ventilação assistida. A incapacidade na alta foi estabelecida pela escala de sete pontos de Hughes. A adesão às recomendações da Comissão de Medicamentos do HCPA, objetivo secundário, foi avaliada através da dose e o esquema de prescrição da IgIV. Resultados: Vinte e cinco participantes (2 a 70 anos) foram incluídos no estudo, cinco tratados com PE, empregando-se Albumina Humana como substituto do plasma, e 20 tratados com IgIV. O custo total do tratamento de um paciente com PE foi R$10.603,88 (± 2.978,12) e o de um que recebeu IgIV foi R$ 32.103,00 (± 21.454,24). O custo total da internação foi de R$45.027,14 (± 32.750,45) para os tratados com PE e de R$ 60.844,28 (±48.590,52) para os que receberam IgIV. Em relação ao desfecho clínico principal, melhora na escala de incapacidade de sete pontos, após o tratamento com uma das alternativas escolhida, a mediana dos pacientes que internaram com grau de gravidade 3 e que foram tratados com PE foi igual a dos que receberam IgIV. Em relação à permanência hospitalar, permanência em UTI e dias de Ventilação Mecânica, não houve diferença estatisticamente significativa entre os dois tratamentos. Conclusões: Quando comparados os custos médios das duas opções terapêuticas, uma delas aparece claramente com menor custo. Quando comparados os desfechos, após o emprego de cada opção terapêutica, estes não revelam diferença. Concluímos que, no HCPA, a opção pelo procedimento Plasmaferese é mais custo efetiva do que o emprego da IgIV. / Objectives: To compare the cost-effectiveness of two distinct therapies, Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) in the treatment of Guillain-Barré Syndrome, concerning the public health care system. Compliance to the guidelines of the Pharmacy and Therapeutics Committee of the Hospital de Clínicas de Porto Alegre was a secondary objective. Methods: A cross-sectional, economical analysis was conducted, including patients treated for GBS in the period from June, 2003 through June, 2008 in Hospital de Clínicas de Porto Alegre (HCPA). The cost-effectiveness of the use of IVIg and PE in such patients was studied through the cost minimization method, considering direct medical costs only (2008 currency), yield by the management of the institution. Patients receiving treatments other than PE or IVIg were excluded. Data were collected by chart reviews. Severity of disease on admittance was classified as follows: mild disease, when the patient was able to walk; moderate disease, when the patient was unable to walk, and severe disease, when assisted ventilation was required. Disability on discharge was established by the 7-point scale of Hughes. Compliance to the guidelines of the Pharmacy and Therapeutics Committee was evaluated through the dose and prescription scheme of IVIg. Results: Twenty-five participants (2 to 70 years of age) were included in the study, 5 were submitted to treatment with PE, using human albumin as replacement for plasma, and 20 were treated with IVIg. The total treatment cost for PE in a single patient was US$6,058.85 (±1,701.78 SD), and the same expense for IVIg was US$18,344.57 (± 12,259.56 SD) (p = 0.035). Total inpatient cost was US$25,729.79 (± 18,714.54 SD) in the PE group, and US$34,768.16 (±27,766.01 SD) (p=0.530) in the IVIg group. The main clinical outcome was improvement in the 7-point disability grade scale. The median of that measure in patients admitted with a severity grade 3 treated either with PE and IVIg was the same. Secondary outcomes, such as in-hospital stay, ICU stay, and number of days on mechanical ventilation revealed no statistically significant difference between treatments. Conclusions: As the mean expenses of both therapeutic options are compared, one clearly stands-out as less onerous. Clinical outcomes, when compared, reveal no statistical difference after each treatment. We concluded that, in HCPA, plasma exchange is more cost-effective than intravenous immunoglobulin.