RESUMO
In the transplant community, research efforts exploring endogenous alternatives to inducing tolerogenic allo-specific immune responses are much needed. In this regard, CD4 + FoxP3+ regulatory T cells (Tregs) are appealing candidates due to their intrinsic natural immunosuppressive qualities. To date, various homeostatic factors that dictate Treg survival and fitness have been elucidated, particularly the non-redundant roles of antigenic CD3ζ/T-cell-receptor, co-stimulatory CD28, and cytokine interleukin (IL-)2 dependent signaling. Many of the additional biological signals that affect Tregs remain to be elucidated, however, especially in the transplant context. Previously, we demonstrated an unexpected link between type I interferons (IFNs) and Tregs in models of multiple myeloma (MM)-where MM plasmacytes escaped immunological surveillance by enhancing type I IFN signaling and precipitating upregulated Treg responses that could be overturned with specific knockdown of type I IFN signaling. Here, we elaborated on these findings by assessing the role of type I IFN signaling (IFN-α and -ß) on Treg homeostasis within an alloimmune context. Specifically, we studied the induction of Tregs from naïve CD4 T cells. Using in vitro and in vivo models of murine skin allotransplantation, we found that type I IFN indeed spatiotemporally enhanced the polarization of naïve CD4 T cells into FoxP3+ Tregs. Notably, however, this effect was not independent of, and rather co-dependent on, ancillary cytokine signals including IL-2. These findings provide evidence for the relevance of type I IFN pathway in modulating FoxP3+ Treg responses and, by extension, stipulate an additional means of facilitating Treg fitness via type I IFNs.
RESUMO
OBJECTIVE: We evaluated 26 patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) with progressive disease despite treatment with cyclophosphamide and steroids treated with additional plasmapheresis and compared outcome with 50 matched-disease controls. METHODS: Patients diagnosed with AAV and treated with cyclophosphamide from January 1990 to December 2009 (n = 272) were included when plasmapheresis was not started at diagnosis but added for progressive disease during initial standard therapy (n = 26). We selected controls equal for age, Birmingham vasculitis activity score, and creatinine at diagnosis. Primary endpoint was estimated glomerular filtration rate (eGFR) or death. RESULTS: Plasmapheresis was added 18 days (range 5-41) after start of therapy. In 11 patients, a rise in serum creatinine >30% led to plasmapheresis; insufficient response to induction (n = 11), progressive pulmonary disease (n = 3), or progressive necrotic lesions (n = 1) were other indications.In the plasmapheresis group, six patients were in need of renal replacement therapy (RRT), and three controls. Five years after diagnosis, four patients had died in the plasmapheresis against eight controls (P = 0.94). At baseline, mean eGFR was 44 ml/min/1.73 m(2) in plasmapheresis group versus 43 ml/min/1.73 m(2) in controls. At start of plasmapheresis, eGFR was 26 ml/min/1.73 m(2) (P = 0.003), at 6 months mean eGFR had significantly improved to 44 ml/min/1.73 m(2) (P = 0.0003), comparable to eGFR in controls, 48 ml/min/1.73 m(2). During long-term follow-up, there was no difference in renal function between the groups. CONCLUSION: AAV patients with progressive disease despite standard induction therapy in whom plasmapheresis was added had significant improvement in renal function and similar long-term outcome in both renal and patient survival as matched disease controls.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Imunossupressores/uso terapêutico , Plasmaferese , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Anticorpos Anticitoplasma de Neutrófilos/análise , Proteína C-Reativa/análise , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Plasmaferese/efeitos adversosRESUMO
Pauci-immune necrotizing glomerulonephritis is the most frequent cause of rapidly progressive glomerulonephritis and, in most cases, is associated with antineutrophil cytoplasmic antibodies (ANCA). It is either the renal manifestation of Wegener's granulomatosis, microscopic polyangiitis of Churg-Strauss syndrome, or a renal-limited vasculitis. In this review, the histopathologic changes seen in renal biopsies of patients with pauci-immune glomerulonephritis are described. The authors also describe why the disease is sometimes limited to the kidneys, the clinical course of renal disease, treatment issues, how to deal with disease relapses, and how to prevent them from occurring. Furthermore, the necessity of renal biopsy and rebiopsy, the usefulness of rapid ANCA detection at diagnosis, and serial measurement of ANCA during follow-up are discussed. The effect of dialysis on the disease process and the possibility of renal transplantation after disease remission are also debated.