RESUMO
Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/uso terapêutico , Rolipram/uso terapêutico , Biomarcadores/metabolismo , Barreira Hematoencefálica/patologia , Proliferação de Células/efeitos dos fármacos , Meios de Contraste , Humanos , Imunofenotipagem , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Inibidores de Fosfodiesterase/efeitos adversos , Rolipram/efeitos adversos , Linfócitos T/patologia , Fatores de Tempo , Falha de TratamentoRESUMO
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by enormous variability in its clinical presentation and course, and for which clear diagnostic parameters are lacking. Here we performed an RNA screen in peripheral mononuclear cells from relapsing-remitting (RR) and primary progressive (PP) MS patients compared with healthy donors (HD) that indicated, among other findings, a role for the chemokine receptor CX3CR1 as a diagnostic marker. Gene expression and flow cytometric analyses demonstrated a significantly lower expression of CX3CR1 in MS patients compared with healthy individuals. The subpopulation of cells responsible for causing this reduced expression of CX3CR1 consisted exclusively of natural killer (NK) cells. Importantly, we found a correlation between disease activity and frequency of CX3CR1-positive NK cells in RRMS patients. These findings emphasize the role of NK cells in the development and course of MS and provide evidence for CX3CR1 expression as a marker for MS patients and disease activity.
