RESUMEN
Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-specific mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/terapia , Interleucina-17/fisiología , Depleción Linfocítica , Linfotoxina-alfa/antagonistas & inhibidores , Células TH1/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Artritis Experimental/terapia , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Inflamación/etiología , Ratones , Ratones Endogámicos DBARESUMEN
Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Citocinas/inmunología , Hipersensibilidad Inmediata/tratamiento farmacológico , Glicoproteínas de Membrana/antagonistas & inhibidores , Ligando OX40/antagonistas & inhibidores , Células Th2/inmunología , Inhibidores del Factor de Necrosis Tumoral , Animales , Anticuerpos Monoclonales/uso terapéutico , Células Cultivadas , Cricetinae , Modelos Animales de Enfermedad , Humanos , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/patología , Inmunoglobulina E/inmunología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Pulmón/inmunología , Pulmón/patología , Macaca mulatta , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ligando OX40/inmunología , Receptores OX40/inmunología , Piel/inmunología , Piel/patología , Células Th2/patología , Factores de Necrosis Tumoral/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.