RESUMO
We investigated the role of 4-1BB, a T cell co-stimulatory molecule, in alloimmune responses. In vivo mixed lymphocyte reactions showed that 4-1BB was preferentially expressed on actively dividing CD4(+) and CD8(+) T cells. Furthermore, following alloantigen challenge, the draining lymph nodes contained subpopulations of 4-1BB-expressing CD4(+) and CD8(+) T cells. 4-1BB-deficient C57BL/6 mice showed a delayed rejection of cardiac transplants mismatched for the major histocompatibility complex. Longer transplant survival was induced by blockade of 4-1BB/4-1BB ligand (4-1BBL) interactions using an anti-4-1BBL monoclonal antibody. Histological analysis showed that prolonged transplant survival in the 4-1BB-deficient and anti-4-1BBL-treated mice correlated with reduced lymphocytic infiltration and vasculitis in the donor heart tissue. Taken together, our data suggest that blockade of 4-1BB/4-1BBL interactions inhibited the expansion of alloreactive T cells and reduced CTL activity against host alloantigen, which in turn resulted in the prolongation of allograft survival. Blockade of the 4-1BB co-stimulatory pathway may be useful for preventing allograft rejection.
Assuntos
Anticorpos Monoclonais/farmacologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Receptores de Fator de Crescimento Neural/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Ligante 4-1BB , Animais , Antígenos CD , Divisão Celular/imunologia , Células Dendríticas/imunologia , Feminino , Rejeição de Enxerto/prevenção & controle , Isoantígenos/imunologia , Isoantígenos/metabolismo , Teste de Cultura Mista de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Mutantes , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/imunologia , Transplante de Pele/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Transplante Homólogo , Membro 9 da Superfamília de Receptores de Fatores de Necrose TumoralAssuntos
Cumarínicos/farmacologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Soluções para Preservação de Órgãos , Preservação de Tecido/métodos , Vitamina E/farmacologia , Adenosina , Alanina Transaminase/análise , Alopurinol , Animais , Anti-Hipertensivos/farmacologia , Sobrevivência Celular , Temperatura Baixa , Glutationa , Hepatócitos/fisiologia , Soluções Hipertônicas , Insulina , Cinética , Malondialdeído/metabolismo , Rafinose , Ratos , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores de TempoRESUMO
Among the phagocytic leukocytes, monocytes have the important role of clearing out parasitic microorganisms. They accomplish this through production of toxic metabolites of oxygen. Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), a peptide that stimulates phosphoinositide (PI) hydrolysis in human leukocytes, including monocytes, binds to a unique cell surface receptor and stimulates superoxide generation, killing of Staphylococcus aureus, and activation of phospholipase D (PLD) in human monocytes. Preincubation of the cells with a PI-specific phospholipase C (PLC) inhibitor (U-73122), protein kinase C inhibitor (GF109203X), or intracellular Ca2+ chelator (BAPTA/AM) before the peptide stimulus totally inhibits the peptide-induced PLD activation and superoxide generation. On the other hand, tyrosine kinase inhibitor genistein only partially inhibits the peptide-induced processes. The peptide-induced bacteria killing activity shares regulatory mechanisms for PLD activation with the superoxide generation, which is inhibited in the presence of 1-butanol. We suggest that the peptide stimulates PLD downstream of PLC activation and PLD activation in turn is essential for the peptide-induced immunological functions such as the superoxide generation and killing of bacteria by human monocytes.