Modelos Experimentais em Transplante

• Ano de defesa: 2009
• Autor(a) principal: Lopes, Camila Takáo [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Imunossupressão; Nefrotoxicidade; Rejeição; Transplante
• Link de acesso: http://repositorio.unifesp.br/handle/11600/9820

The association of new compounds with lower doses of current immunosuppressive drugs used in transplantation might increase their potential in preventing rejection episodes and lead to decreased side effects. Sirolimus (SRL) increases allograft survival by blocking activated T cell proliferation, but it causes side effects like hypertension, peripheral edema and proteinuria. FTY720 (FTY), a new immunomodulator, increases experimental allograft survival by impairing lymphocyte migration towards the inflammatory site (graft) without undermining their activation. Our study had for aim to evaluate semi-allogeneic murine skin allograft survival (F1 donor and C57BL/6 recipient) under prolonged administration (21 days) of FTY+SRL, the immunological events associated with allograft survival and the effects of these drugs on renal parameters. Allograft survival was significantly increased by monotherapies (p<0.0005) or combined administration (p<0.0005). FTY+SRL Group presented only one episode of rejection. The increased survival was related to lower percentage of lymphocytes in the peripheral blood (p<0.005) due to decreased percentages of CD3+CD4+ (p<0.005) and CD3+CD8+ (p<0.005) lymphocytes. On the other hand, the percentage of CD11b+ was significantly increased (p<0.005). In the lymph nodes, FTY+SRL-treated animals presented significantly lower number of CD3+CD4+ (p<0.005) and CD3+CD8+ (p<0.005) lymphocytes. In the spleen, there was decreased number of total splenocytes (p<0.005) due to lower numbers of CD3+CD4+ (p<0.005) and CD3+CD8+ (p<0.005) lymphocytes and CD11b+ cells (P<0.005). In the thymus, FTY+SRL presented significantly decreased number of total thymocytes (p<0.005) due to diminished number of CD4+CD8+ cells (p<0.005). In the graft, FTY+SRL significantly lower CD3+CD4+ cell percentages (p<0.05) and presented a trend towards a decrease of CD11b+ cell percentages (p=0.056). Serum creatinine concentration was increased in FTY+SRL-treated animals (p<0.05), but there were no alterations of 24-hour urinary volume, urinary creatinine or protein concentrations or structure alterations. In summary, FTY+SRL combination was effective in increasing semi-allogeneic murine skin allograft survival. The suggested immunological events associated with this finding were the decrease of CD3+CD4+ and CD3+CD8+ cell numbers in the peripheral blood; retention of recipient antigen presenting cell (CD11b+) in the peripheral blood, preventing their migration to lymph nodes and spleen, decreasing the allostimulatory activity of the recipient’s naive T cells; impairment of donor DC migration to the secondary lymphoid organs and decrease of antigen presentation; prevention of mature thymocyte egress to the periphery and CD4+CD8+ immature thymocyte apoptosis; possible selection of cells with regulatory phenotype infiltrating the graft. The drug combination was not associated with impairment of kidney functions or structure.