Thesis (Ph. D.)--Case Western Reserve University, 2004. / [School of Medicine] Department of Pathology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Chronic rejection is a major obstacle to long-term survival of organ transplants. PPAR-γ agonist rosiglitazone has been shown to reduce graft rejection but the underlying mechanisms remain unclear. Combined treatment of rosiglitazone and anti-IL-5 antibody prevented MHC class II histoincompatiblecardiac graft rejection with a reduction of cellular infiltration, vasculopathy and interstitial fibrosis in a heterotopic heart transplantation model. In particularly, rosiglitazone decreased CD8 T cells infiltration and luminal occlusion, while anti-IL-5 antibody reduced eosinophil infiltration and collagen deposition. Adiponectin gene (APN) is a PPAR-γ target gene, and the expression of APN receptor AdipoRII in grafts, dendritic cells (DCs) and T cells are increased by rosiglitazone. These findings prompted me to further examine the immunomodulatory role of APN in graft rejection. APN is an anti-inflammatory adipocytokine, and has been shown to inhibitimmunostimulatory function of monocytes and macrophages. Rosiglitazone suppresses DCs maturation, activation and proliferation;hence, it is possible that APN could protect graft rejection through immunoregulation of DCs. Here, using in vitro culture systems, I found that APN has only moderate effect on the differentiation of bone marrow derived DCs but itcould alter DC phenotypes. APN-treated DCs showed an increased expression of PD-L1, which is consistent with the increased PD-L1 expression in rosiglitazone treated cardiac allografts. APN-treated DCs led to a decreased proliferation and reduction of IL-2production of T cell. Moreover, APN-treated DCs increased the expansion of Tregs (regulatory T cells) which could be inhibited by the blockage of PD-1/PD-L1 pathway, suggesting that PD-1/PD-L1 pathway and expansion of Tregs played important roles in APN-treated DCs mediated immunomodulation. Further, I employed APN-/-mice for functional and mechanistic studies, and found that cardiac allografts were not rejected by APN-/-recipient mice even after 120 days post-transplantation. Histological analyses revealed very little eosinophils, CD4 and CD8 T cells infiltration; no collagen deposit and no vessel occlusion in the cardiac allografts. Furthermore, Th2 cytokines such as IL-4 and IL-5 were lower in cardiac allografts and in the serum of APN-/-recipient. Inhibition of AMPK signaling, a major APN mediated pathway, reduced the eosinophils infiltration in wild type recipient. In contrast, AMPK activation increased eosinophils infiltration in APN-null recipient. APN enhanced T cell proliferation. AMPK and P38MAPK inhibitors as well as anti-IL-4 antibody inhibited APN-induced T cell proliferation. P38 MAPK inhibitors reduced IL-4 production in mature DCs but enhanced IL-4 expression in immature DCs. In EL-4 T cells, APN increased nuclear expressions of GATA-3 and p-STAT6 and augmented IL-4 expression, and the phenomenon was suppressed by target specific knockdown of AdipoR I and II. In summary, current study provides new mechanistic insights of PPAR-γ activation and APN signaling in the modulation of adaptive and transplantation immunity, establishing a link between metabolism and immune regulation. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph.D.)--Flinders University, School of Medicine, Dept. of Ophthalmology. / Typescript bound. Includes bibliographical references: (leaves 258-281) Also available online.

Orientador: Salomon Soriano Ordinola Rojas / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T00:59:13Z (GMT). No. of bitstreams: 1 Miguel_GabrielAntonioStanisci_M.pdf: 2975905 bytes, checksum: c45b885c0ebe455da2be8fded7817e46 (MD5) Previous issue date: 2009 / Resumo: Introdução: O transplante (TX) cardíaco é uma alternativa para os indivíduos com doença cardíaca terminal. Na evolução pós-TX, a ocorrência de episódios de rejeição é um evento frequente, sendo responsável pelo aumento da morbimortalidade. Uma alternativa relevante seria o emprego de um exame não invasivo que tivesse uma boa acurácia na detecção das alterações da função sisto-diastólica do coração transplantado, pois a biópsia endomiocárdica (BEM) não é um procedimento isento de complicações. Objetivo: Comparar a função ventricular esquerda entre os pacientes transplantados com rejeição cardíaca e os pacientes transplantados sem rejeição; utilizando como referência o grupo controle e correlaciona-la com rejeição cardíaca imunológica. Métodos: Foram realizados ecocardiogramas transtorácicos no período de janeiro de 2006 a janeiro de 2008, para a avaliação prospectiva de 47 pacientes; sendo 17 pacientes (36,2 %) pertencentes ao grupo controle (grupo GC), 18 (38,3%) pertencentes ao grupo de pacientes transplantados sem rejeição (TX0) e 12 (25,5%) pertencentes ao grupo de pacientes transplantados com rejeição (TX1). Comparou-se a função sisto-diastólica entre os três grupos (GC, TX0, TX1). Para o estudo da homogeneidade entre proporções foi utilizado o teste exato de Fisher. Para a análise da hipótese de igualdade entre os grupos em relação às medianas, utilizou-se o teste não-paramétrico de Kruskal-Wallis seguido do teste de comparações múltiplas. O nível de significância utilizado para os testes foi de 5%. Resultados: Os grupos não diferiram em relação à idade [34,0 (29,5 - 44,0) X 46,0 (33,5 - 51,5) X 39,0 (32,5 - 54,5) p = 0,354], ao peso [70,0 (57,5 - 85,0) X 66,5 (57,5 - 88,0) X 61,0 (57,5 - 73,5) p = 0,661], altura [1,65 (1,59 - 1,73) X 1,66 (1,64 - 1,70) X 1,69 (1,64 - 1,72) p = 0,821] e superfície corpórea [1,84 (1,58 - 1,98) X 1,75 (1,62 - 2,03) X 1,69 (1,63 - 1,88) p = 0,758]. O grupo GC quando comparado com o grupo TX0, apresentou alteração da função sisto-diastólica do ventrículo esquerdo, expressa através do aumento do Índice de Performance Miocádica (IPM), sendo esta mais significativa nos pacientes do grupo TX1 [0,38 (0,29 - 0,44) X 0,47 (0,43 - 0,56) X 0,58 (0,52 - 0,74) p <0,001]. Conclusão: Foi evidenciado que o Índice de Performance Miocárdica encontra-se aumentado nos pacientes transplantados, em relação ao grupo controle e não houve diferença significativa entre os dois grupos de pacientes transplantados; portanto, o ecocardiograma mostrou-se como exame de boa acurácia na detecção das alterações da função sisto-diastólica do coração transplantado e não foi confiável como método substituto da biópsia endomiocárdica para o diagnóstico seguro de rejeição cardíaca. / Abstract: Introduction: The transplant (TX) cardiac is an alternative for the individuals with terminal cardiac illness. In the evolution after TX, the occurrence of rejection episodes is a frequent event, being responsible for the increase of morbi-mortality. An excellent alternative would be the job of a not invasive examination that had a good acurácia in the detention of the alterations of the diastolic function of the transplantated heart, therefore the endomyocardial biopsy (BEM) is not an exempt procedure of complications. Objective: Compare the left ventricular function between patients transplated with rejection and cardiac transplant patients without rejection, using as reference the control group and correlated it with immunological rejection rate. Methods: Transthoracic echocardiograms in the period of January of 2006 had been carried through the January of 2008, for the prospective evaluation of 47 patients; being 17 patients (36,2 %) pertaining to the group it has controlled (group GC), 18 (38,3%) pertaining to the group of patients transplantated without rejection (TX0) and 12 (25,5%) pertaining ones to the group of patients transplantated with rejection (TX1). It was compared sisto-diastolic function between the three groups (GC, TX0, TX1). To study the homogeneity of proportions was used Fisher's exact test. For the analysis the hypothesis of equality between the groups in relation to the medians, we used the nonparametric Kruskal-Wallis test followed by multiple comparisons. The significance level used for the tests was 5%. Results: The groups did not differ in age [34.0 (29.5 to 44.0) X 46.0 (33.5 - 51.5) X 39.0 (32.5 - 54.5) p = 0.354 ], weight [70.0 (57.5 to 85.0) X 66.5 (57.5 to 88.0) X 61.0 (57.5 to 73.5) p = 0.661], height [ 1.65 (1.59 to 1.73) X 1.66 (1.64 - 1.70) X 1.69 (1.64 - 1.72) p = 0.821] and body surface area [1.84 ( 1.58 to 1.98) X 1.75 (1.62 - 2.03) X 1.69 (1.63 to 1.88) p = 0.758]. The GC group compared with the group TX0, had an alteration of the systolic-diastolic function of left ventricle, expressed by increasing the Miocardic Performance Index (IPM), which is more significant for patients in group TX1 [0.38 (0, 29 to 0.44) X 0.47 (0.43 to 0.56) X 0.58 (0.52 to 0.74) p <0.001]. Conclusion: It was shown that the myocardial performance index is increased in transplant patients in the control group and no significant difference between the two groups of transplant patients, so the echocardiogram showed to be taking good accuracy in the detection of systolic-diastolic function of the transplanted heart and was not a reliable method of biopsy substitute for the confident diagnosis of cardiac rejection. / Mestrado / Cirurgia / Mestre em Cirurgia

Orientador: Salomón Soriano Ordinola Rojas / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T03:31:12Z (GMT). No. of bitstreams: 1 Miguel_GabrielAntonioStanisci_D.pdf: 3265608 bytes, checksum: 8e5fab35107186e1c25936f84d45682f (MD5) Previous issue date: 2013 / Resumo: Introdução: O transplante (TC) cardíaco é uma alternativa para os indivíduos com doença cardíaca terminal. Na evolução pós-TC, a ocorrência de episódios de rejeição é um evento frequente, sendo responsável pelo aumento da morbi-mortalidade. Uma alternativa relevante seria o emprego de um exame não invasivo que tivesse uma boa acurácia na detecção das alterações da função sisto-diastólica do coração transplantado, pois a biópsia endomiocárdica (BEM) não é um procedimento isento de complicações. Objetivo: Analisar o Índice de Performance Miocárdica como ferramenta para o diagnóstico de rejeição cardíaca e demonstrar sua possibilidade de triagem na seleção de pacientes para BEM. Método: Foram realizados ecocardiogramas transtorácicos no período de janeiro de 2006 a janeiro de 2008, para a avaliação prospectiva de 58 pacientes; sendo 17 pacientes (29,3 %) pertencentes ao grupo controle (grupo GC), 22 (37,9%) pertencentes ao grupo de pacientes transplantados sem rejeição (TX0) e 19 (32,9%) pertencentes ao grupo de pacientes transplantados com rejeição (TX1). Comparou-se a função sisto-diastólica entre os três grupos (GC, TX0, TX1). O teste de Qui-quadrado foi utilizado para verificar se as proporções de gênero e raça eram homogêneas. Para a comparação entre os três grupos, foi utilizado a ANOVA, em caso de normalidade (verificada por meio do teste de Kolmogorov-Smirnov) e homocedasticidade (verificada por meio do teste de Levene) entre as variáveis; caso contrário, optou-se por utilizar o teste não-paramétrico de Kruskal-Wallis. O nível de significância utilizado para os testes foi de 5%. Resultados: Os grupos não diferiram em relação à idade [38,47 (±11,17) X 41,18 (±13,83) X 45,95 (±12,87) p = 0,212], ao peso [71,95 (±15,90) X 68,68 (±13,14) X 66,09 (±11,91) p = 0,442], altura [1,66 (±0,11) X 1,67 (±0,05) X 1,68 (±0,06) p = 0,894] e superfície corpórea [1,82 (±0,25) X 1,78 (±0,18) X 1,75 (±0,17) p = 0,603]. O grupo GC quando comparado com o grupo TX0, apresentou alteração da função sisto-diastólica do ventrículo esquerdo, expressa através do aumento do IPM, sendo esta mais intensa nos pacientes do grupo TX1 [0,38 (0,29 - 0,39) X 0,47 (0,42 - 0,49) X 0,60 (0,52 - 0,71) p <0,001]. Conclusão: Foi evidenciado que o ÍPM encontra-se bastante aumentado nos pacientes transplantados com rejeição em relação aos pacientes transplantados sem rejeição e também em relação ao controle; portanto, este índice mostrou-se como informação não invasiva e de boa acurácia na detecção das alterações da função sisto-diastólica do coração transplantado, podendo auxiliar na triagem de pacientes transplantados, clinicamente descompensados e que anteriormente seriam submetidos à biópsia de rotina / Abstract: Introduction: The transplant (TC) cardiac is an alternative for the individuals with terminal cardiac illness. In the evolution after TC, the occurrence of rejection episodes is a frequent event, being responsible for the increase of morbi-mortality. An excellent alternative would be the job of a not invasive examination that had a good acurácia in the detention of the alterations of the diastolic function of the transplantated heart, therefore the endomyocardial biopsy (EMB) is not an exempt procedure of complications. Objective: Analyze the Myocardial Performance Index (MPI) as a tool for the diagnosis of cardiac rejection and demonstrate their ability to triage in the selection of patients for EMB. Methods: Transthoracic echocardiograms in the period of January of 2006 had been carried through the January of 2008, for the prospective evaluation of 58 patients; being 17 patients (29,3%) pertaining to the group it has controlled (group GC), 22 (37,9%) pertaining to the group of patients transplantated without rejection (TX0) and 19 (32,9%) pertaining ones to the group of patients transplantated with rejection (TX1). It was compared sisto-diastolic function between the three groups (GC, TX0, TX1). The Qui-quadrado test was used to verify that the proportions of gender and race were homogeneous. For comparison between groups, ANOVA was used, in case of normality (verified by the Kolmogorov-Smirnov test) and homoscedasticity (verified by Levene's test) between the variables; otherwise opted to using the nonparametric Kruskal-Wallis test. The significance level used for the tests was 5% Results: The groups did not differ in age [38,47 (±11,17) X 41,18 (±13,83) X 45,95 (±12,87) p = 0,212], weight [71,95 (±15,90) X 68,68 (±13,14) X 66,09 (±11,91) p = 0,442], height [1,66 (±0,11) X 1,67 (±0,05) X 1,68 (±0,06) p = 0,894] and body surface area [1,82 (±0,25) X 1,78 (±0,18) X 1,75 (±0,17) p = 0,603]. The GC group compared with the group TX0, had an alteration of the systolic-diastolic function of left ventricle, expressed by increasing the Miocardic Performance Index (IPM), which is more significant for patients in group TX1 [0,38 (0,29 - 0,39) X 0,47 (0,42 - 0,49) X 0,60 (0,52 - 0,71) p <0,001]. Conclusion: It was shown that the PMI is greatly increased in patients with transplant rejection compared to patients transplanted without rejection and also in relation to the control, so this index proved to be as non-invasive and accurate method for the detection of changes in systolic and diastolic function of the transplanted heart to assist in screening transplant patients clinically decompensated and who previously underwent biopsy would be routine / Doutorado / Fisiopatologia Cirúrgica / Doutor em Ciências

M.A. (Psychology) / The purpose of this study was to determine whether psychological factors contribute to the rejection of a transplanted kidney. After a review of existing literature on the relationship between various psychological factors and immunological system of the body, it was hypothesized that psychological factors such as state- and trait anxiety, stress, locus of control as well as hopelessness would affect immune responses, and therefore contribute to the acceptance or rejection of a transplanted kidney. In order to test the hypothesis, patients of the Johannesburg Hospital undergoing haemodialysis and on the waiting list for kidney transplant were tested. Out of the initial sample, 12 of these patients, who had undergone a renal transplant, were used in the study. Out of the 12 patients, 6 patients had accepted the graft, while 6 patients had rejected the graft. The tests used in the study were the Spielberger State-Trait Anxiety Scale, Hopelessness Scale, Health Locus of Control and the Rotter Internal-External Locus of Control Scale. The analysis of the data indicated a significant difference in the mean score for the two groups with relation to state anxiety, trait anxiety and health locus of control. The results indicated that the higher the state and trait anxiety, and the more internal the health locus of control of the patient, the greater the chances that the graft would be accepted. The results of this study indicated that psychological factors do contribute to the immune response of the body to a transplanted kidney. This would imply that more research is necessary to establish influence of various psychological as well as social variables in transplants and medical immunology.

No description available.

The aims of the present investigation are fourfold: (i) to review the range of non-invasive methods that may be used to diagnose acute cardiac allograft rejection; (ii) to review the use of the bioptome in sampling the donor heart endomyocardium; (iii) to review the light microscopic and histological grading of acute cardiac rejection; (iv) to characterise the mononuclear populations in endomyocardial biopsy samples and correlate the findings with the light microscopic appearances of the same biopsy specimens.