Testes prognosticos de rejeição e doença do enxerto contra o hospedeiro em transplantes de celulas progenitoras hematopoieticas com doadores HLA identicos / \ Jeane Eliete Laguila Visentainer
TESE
Português
(Broch.)
T/UNICAMP V823t
Campinas, SP : [s.n.], 2003.
173p. : il.
Orientador: Carmino Antonio de Souza
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Resumo:O transplante alogênico de células progenitoras hematopoiéticas é o tratamento de escolha para muitas doenças hematológicas e imunodeficiências primárias. A seleção de doadores é baseada na definição de moléculas HLA-A e B por sorologia, de alelos HLA-DRB1 e DQB1 por técnicas de biologia...
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Resumo:O transplante alogênico de células progenitoras hematopoiéticas é o tratamento de escolha para muitas doenças hematológicas e imunodeficiências primárias. A seleção de doadores é baseada na definição de moléculas HLA-A e B por sorologia, de alelos HLA-DRB1 e DQB1 por técnicas de biologia molecular e na cultura mista de linfócitos. Apesar disto, a doença do enxerto contra o hospedeiro (GVHD) é ainda uma grave complicação, que ocorre em aproximadamente 35% dos receptores de medula HLA-idênticos. O presente estudo teve por objetivo avaliar o poder prognóstico da ocorrência de rejeição e GVHD dos seguintes testes laboratoriais: (1) cultura mista de linfócitos clássica (CML) e potencializada com citocinas exógenas (CMLp); (2) tipagem de genes de citocinas, pela técnica de PCR-SSP e (3) seguimento do nível sérico de citocinas dos pacientes transplantados, empregando-se métodos imunoenzimáticos quantitativos. No estudo, foram avaliados 118 transplantes, com doadores HLA-idênticos, realizados no Centro de Hematologia e Hemoterapia e Hospital de Clínicas da Universidade Estadual de Campinas, de agosto de 1994 a fevereiro de 2002. Na CMLp, a resposta dos linfócitos do doador contra as células do receptor (DxR) foi aumentada 1,9 e 4,1 vezes, com a adição de IL-4 (100 hg/mL) e IL-2 (10 hg/mL), respectivamente. Todavia, a resposta do doador contra suas próprias células (DxD) também sofreu um incremento de 2,0 e 6,4 vezes, respectivamente. Como o tratamento avaliado também induziu aumento das respostas autólogas, o emprego da CMLp não trouxe vantagens adicionais ao método tradicional (CML), que mostrou correlação com a incidência de GVHD crônica. A análise do polimorfismo dos genes reguladores de citocinas mostrou que, os genótipos de TNF-a-308, IFN-g+874, IL-6-174, IL-10-1082, -819, -592 e TGF-b1+869, +915 não foram associados ao risco aumentado de GVHD aguda e rejeição, enquanto o fenótipo de baixo produtor de IL-6 mostrou associação com GVHD crônica. O acompanhamento da variação dos níveis séricos de sIL-2R, IL-6, IL-10, TNF-a, IFN-g e TGF-b1 dos receptores até 15 semanas pós-transplante revelou que, os níveis médios de sIL-2R e IL-10 foram maiores no grupo que desenvolveu GVHD aguda (776,4 ± 65,5 rg/mL e 10,9 ± 3,3 rg/mL) em relação ao grupo que não desenvolveu esta doença (541,1 ± 17,3 rg/mL e 2,5 ± 2,2 rg/mL). Os níveis de sIL-2R no período de ¿pega¿ do enxerto (1.165,0 ± 179,2 rg/ml vs. 578,0 ± 47,2 rg/ml) e ao tempo da GVHD aguda (926,4 ± 142,5 rg/ml vs. 496,5 ± 48,7rg/ml) também diferiram entre os grupos. A cinética destas citocinas também revelou que os níveis de TNF-a e TGF-b1 foram correlacionados com GVHD aguda. Nas primeiras semanas após o transplante, os níveis de TNF-a foram associados a GVHD aguda (72,7 ± 2,6 rg/mL vs. 38,1 ± 1,7 rg/mL). Nas últimas semanas, os níveis de TGF-b1 foram menores no grupo que desenvolveu a GVHD aguda (7,5 ± 1,4 hg/ml), comparado ao grupo sem a doença (17,0 ± 1,6 hg/ml). Assim sendo, o monitoramento dos níveis séricos de sIL-2R, IL-10, TNF-a e TGF-b1 poderia fornecer ao clínico um indicativo do risco de GVHD aguda, enquanto a genotipagem de IL-6-174 poderia oferecer um novo método para identificar pacientes ao risco de GVHD crônica
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Abstract: Allogeneic hematopoietic stem cell transplantation is the chosen treatment for many hematological diseases and primary immunodeficiency¿s. The donor¿s selection has been based on the serological definition of HLA-A and B, in the definition of
HLA-DRB1 and DQB1 by DNA-based molecular... Ver mais Abstract: Allogeneic hematopoietic stem cell transplantation is the chosen treatment for many hematological diseases and primary immunodeficiency¿s. The donor¿s selection has been based on the serological definition of HLA-A and B, in the definition of
HLA-DRB1 and DQB1 by DNA-based molecular method and in the standard mixed lymphocyte culture. Regardless, the graft-versus-host disease (GVHD) is still one of the several complications that occur in approximately 35% of HLA-identical bone marrow recipients. The objective of this study was to evaluate the prognostic power of rejection and GVHD development of laboratorial assays: (1) standard mixed lymphocyte culture (MLC) and potencialized (MLCp) with exogenous cytokines; (2) typing of cytokine genes, by PCR-SSP, and (3) following-up of serum level cytokines from transplanted patients, using quantitative enzyme-linked immunoassays. From August 1994 to February 2002, it was analyzed 118 transplants, with HLA-identical donors, who had been performed in the Hematological and Hemotherapy Center and Clinic¿s Hospital at Campinas State University. In the MLCp, the donor lymphocyte response versus receptor cells (DxR) was augmented 1.9 and 4.1 times with IL-4 (100 hg/mL) and IL-2 (10 hg/mL) supplementation, respectively. However, the donor response versus their selves-cells (DxD) also augmented, 2.0 and 6.4 times, respectively. Since this treatment also stimulated an increase of autologous responses, MLCp did not have advantages on relation to standard method (MLC) that showed a correlation with the incidence of chronic GVHD. Cytokine gene polymorphism analysis showed that TNF-a-308, IFN-g+874, IL-6-174, IL-10-1082, -819, -592, and TGF-b1+869, +915 genotypes were not associated to increased risk of acute GVHD and rejection, whereas the IL-6 low producer phenotype showed significant statistical association to chronic GVHD. The following-up of sIL-2R, IL-6, IL-10, TNF-a, IFN-g, and TGF-b1 recipient serum levels during 15 weeks post-transplant showed that sIL-2R and IL-10 average levels were higher in the group with acute GVHD (776.4 ± 65.5 rg/mL and 10.9 ± 3.3 rg/mL), than in the group without the disease (541.1 ± 17.3 rg/mL and 2.5 ± 2.2 rg/mL). Soluble IL-2 receptor levels at the engraftment and at onset of acute GVHD were also different between the groups with and without acute GVHD (1.165.0 ± 179.2 rg/ml vs. 578.0 ± 47.2 rg/ml and 926.4 ± 142.5 rg/ml vs. 496.5 ± 48.7rg/ml), respectively. The cytokine kinetics also showed that TNF-a and TGF-b1 levels were associated with acute GVHD. In the first weeks after the transplant, high TNF-a levels were associated with acute GVHD (72.7 ± 2.6 rg/mL vs. 38.1 ± 1.7 rg/mL). In the last weeks, TGF-b1 levels were lower in the group with acute GVHD (7.5 ± 1.4 hg/ml) than those in the group without the disease (17.0 ± 1.6 hg/ml). Therefore, the monitoring of sIL-2R, IL-10, TNF-a, and TGF-b1 serum levels after the transplant can provide to physician an indication of acute GVHD risk, while IL-6-174 genotype may offer a new method for identifying patients at increased risk of chronic GVHD Ver menos
HLA-DRB1 and DQB1 by DNA-based molecular... Ver mais Abstract: Allogeneic hematopoietic stem cell transplantation is the chosen treatment for many hematological diseases and primary immunodeficiency¿s. The donor¿s selection has been based on the serological definition of HLA-A and B, in the definition of
HLA-DRB1 and DQB1 by DNA-based molecular method and in the standard mixed lymphocyte culture. Regardless, the graft-versus-host disease (GVHD) is still one of the several complications that occur in approximately 35% of HLA-identical bone marrow recipients. The objective of this study was to evaluate the prognostic power of rejection and GVHD development of laboratorial assays: (1) standard mixed lymphocyte culture (MLC) and potencialized (MLCp) with exogenous cytokines; (2) typing of cytokine genes, by PCR-SSP, and (3) following-up of serum level cytokines from transplanted patients, using quantitative enzyme-linked immunoassays. From August 1994 to February 2002, it was analyzed 118 transplants, with HLA-identical donors, who had been performed in the Hematological and Hemotherapy Center and Clinic¿s Hospital at Campinas State University. In the MLCp, the donor lymphocyte response versus receptor cells (DxR) was augmented 1.9 and 4.1 times with IL-4 (100 hg/mL) and IL-2 (10 hg/mL) supplementation, respectively. However, the donor response versus their selves-cells (DxD) also augmented, 2.0 and 6.4 times, respectively. Since this treatment also stimulated an increase of autologous responses, MLCp did not have advantages on relation to standard method (MLC) that showed a correlation with the incidence of chronic GVHD. Cytokine gene polymorphism analysis showed that TNF-a-308, IFN-g+874, IL-6-174, IL-10-1082, -819, -592, and TGF-b1+869, +915 genotypes were not associated to increased risk of acute GVHD and rejection, whereas the IL-6 low producer phenotype showed significant statistical association to chronic GVHD. The following-up of sIL-2R, IL-6, IL-10, TNF-a, IFN-g, and TGF-b1 recipient serum levels during 15 weeks post-transplant showed that sIL-2R and IL-10 average levels were higher in the group with acute GVHD (776.4 ± 65.5 rg/mL and 10.9 ± 3.3 rg/mL), than in the group without the disease (541.1 ± 17.3 rg/mL and 2.5 ± 2.2 rg/mL). Soluble IL-2 receptor levels at the engraftment and at onset of acute GVHD were also different between the groups with and without acute GVHD (1.165.0 ± 179.2 rg/ml vs. 578.0 ± 47.2 rg/ml and 926.4 ± 142.5 rg/ml vs. 496.5 ± 48.7rg/ml), respectively. The cytokine kinetics also showed that TNF-a and TGF-b1 levels were associated with acute GVHD. In the first weeks after the transplant, high TNF-a levels were associated with acute GVHD (72.7 ± 2.6 rg/mL vs. 38.1 ± 1.7 rg/mL). In the last weeks, TGF-b1 levels were lower in the group with acute GVHD (7.5 ± 1.4 hg/ml) than those in the group without the disease (17.0 ± 1.6 hg/ml). Therefore, the monitoring of sIL-2R, IL-10, TNF-a, and TGF-b1 serum levels after the transplant can provide to physician an indication of acute GVHD risk, while IL-6-174 genotype may offer a new method for identifying patients at increased risk of chronic GVHD Ver menos
Souza, Carmino Antonio de, 1951-
Orientador
Dulley, Frederico
Avaliador
Daher, Silvia
Avaliador
Lieber, Sofia Rocha
Avaliador
Marques Junior, Jose Francisco Comenalli
Avaliador
Testes prognosticos de rejeição e doença do enxerto contra o hospedeiro em transplantes de celulas progenitoras hematopoieticas com doadores HLA identicos / \ Jeane Eliete Laguila Visentainer
Testes prognosticos de rejeição e doença do enxerto contra o hospedeiro em transplantes de celulas progenitoras hematopoieticas com doadores HLA identicos / \ Jeane Eliete Laguila Visentainer
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