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.

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[1][2][3][4] Since approval of a depleting anti-CD20 monoclonal antibody (mAb) (rituximab [Genentech, South San Francisco, CA; Biogen-IDEC, Cambridge, MA; Roche, Basel, Switzerland)] in 1997 for the treatment of non-Hodgkin lymphoma (NHL), almost 1 million patients have been treated with rituximab as a first or second line therapy, either alone or in combination with chemotherapy. In addition, rituximab maintenance therapy significantly prolongs tumor remission and patient survival in patients with indolent B-cell NHL or chronic lymphocytic leukemia (CLL). 5,6 More recently, rituximab has demonstrated clinical benefit in a variety of autoimmune diseases including rheumatoid arthritis, pemphigus vulgaris, immune thrombocytopenia and autoimmune hemolytic anemia. 4,7,8 As a result, understanding the contribution of B lymphocytes to human autoimmune diseases received revived interest, and several mechanisms have been postulated to participate in disease pathogenesis, including autoantibody production, B-cell antigen presentation, cytokine generation, and lymphorganogenesis. 2,3,9,10 Inhibition of different combinations of these mechanisms is probably responsible for clinical benefit.The success of anti-CD20 B-cell immunotherapy spearheaded a large number of preclinical and clinical efforts to understand in vivo mechanisms of drug activity. Direct elimination of malignant B cells through antigen-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and apoptosis have been demonstrated as the main mechanisms of action in a variety of systems including mouse xenotumors and normal mouse and nonhuman primate (NHP) B-cell subsets. 11-15 Two major determinants affecting normal mouse B-cell depletion have been identified. 13,16 First, the kinetics of B-cell recirculation determines the speed and magnitude of anti-CD20 mAb-mediated B-cell depletion. Cells with higher recirculatory kinetics from blood, lymph nodes, and spleen follicular areas are depleted faster and more completely than cells with lower recirculatory kinetics (eg, peritoneal cavity [PEC], marginal zone [MZ], germinal centers [GC]). Second, the local microenvironment influences the extent of B-cell depletion. Marginal zone, Peyer patches (PP), germinal center, memory, and peritoneal cavity B cells exhibit greater resistance to depletion in mice and nonhuman primates. Reduced recruitment of effector mechanisms in the peritoneal cavity as well as intrinsic B1 B cells properties appear to cause the slower kinetics and B-cell reduction after anti-CD20 mAb treatment. 16 Differences across mouse strains and epitopes recognized by anti-CD20 antibodies used for depletion might explain the differential effects seen on mouse splenic marginal zone B cells. 13,16 Small but consistent numbers of residual B cells can be detected in most lymphoid organs in mice and primates treated with anti-CD20 mAbs. One possibility of achieving a more complete B-cell reduction would be to block B-cell survival signals in addition to Submitted April 30, 2007...

A primary series of 1 or 2 IPV doses followed by 2 or 1 OPV doses was immunogenic and noninferior to an OPV-only arm. SSBA was better at detecting antibodies elicited by OPV with antibody titers correlated to the number of OPV doses (NCT01475539).

OX40L-OX40 interactions have been shown to be important for development of Th2-mediated diseases such as asthma through the use of mouse models in vivo. Thymic Stromal LymphoPoietin (TSLP), an IL7-like cytokine, has been shown to potently induce atopic immune responses and is highly expressed at sites of allergic inflammation. While the ability of TSLP to effectively induce an atopic immune cascade has been demonstrated through the use of transgenic mice, direct downstream in vivo mediators have not been identified. In our current study, we show that OX40L is a critical mediator of TSLP-mediated Th2 responses not only in vitro but also in vivo. TSLP strongly induces OX40L expression on dendritic cells and blocking a-OX40L antibodies efficiently inhibit Th2 responses induced by TSLP in vitro, and in the lung and skin in vivo. Inhibition of OX40L function was also very efficacious in decreasing Th2 cytokines and antigen-specific IgE in a mouse model of OVA-induced asthma. The use of blocking a-OX40L antibodies thus presents an effective strategy for the treatment of allergic disease associated with dysregulated Th2 immune responses. The source of research support is Genentech, Inc.