RESUMEN
Therapy with tumour necrosis factor-alpha (TNFalpha)-blocking agents is successful in treating inflammatory disorders, but carries an increased risk of manifest and reactivating infection with intracellular bacteria. In a mouse model of latent Salmonella typhimurium infection, neutralization of TNFalpha did not result in reactivation of infection, suggesting only a minor role for TNFalpha during latency of persistent Salmonella infection.
Asunto(s)
Inmunoglobulina G/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Salmonelosis Animal/inmunología , Salmonelosis Animal/prevención & control , Salmonella typhimurium/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Anticuerpos Bloqueadores/administración & dosificación , Línea Celular , Etanercept , Inmunoglobulina G/administración & dosificación , Inyecciones Intraperitoneales , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C3H , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Recurrencia , Salmonelosis Animal/microbiología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
OBJECTIVE: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. METHODS: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. RESULTS: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. CONCLUSIONS: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.
