SUMMARY SUMMARYProtective immunity is provided by the interplay between the innate and the adaptive arms of the immune systems. The innate as well as the adaptive immune response is regulated by specialized cells with the challenging task to eliminate pathogens while not damaging the host itself. Usually the immune system copes well with this charge, but is not always successful. Furthermore, proinflammatory lipids, cytokines, and chemokines are produced and released, leading to an allergic inflammation. Although frequency of individuals suffering from allergies has increased exponentially over the last century, the only available therapy that stops disease progression is allergen-specific immunotherapy (SIT). Even though allergenspecific antibodies have been reported to play an important role in SIT, mechanisms of IgGmediated inhibition of allergic reactions are not well defined.The present studies aimed to provide better understanding of the mechanisms how allergenspecific IgG antibodies may modulate allergic responses. Therefore, we generated monoclonal antibodies (mAbs) that recognize three non-overlapping epitopes on the major cat allergen Feld1. Each of the three mAbs was produced as IgE or different IgG isotypes. We found that IgE antibodies against two non-overlapping epitopes on Feld1 were required and sufficient to sensitize mast cells for maximal activation upon exposure to monomeric Feld1.

Dendritic cell (DC)-based immunotherapy of malignant diseases relies on 2 critical parameters: antigen transport from the periphery to draining lymph nodes and efficient priming of primary and stimulation of secondary immune responses. Prostaglandin E 2 (PGE 2 ) signaling has been shown to be pivotal for DC migration toward lymph node-derived chemokines in vitro and in vivo. Here, we demonstrate that PGE 2 induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE 2 early during DC maturation was sufficient to induce the costimulatory molecules. The expression of the costimulatory molecules was independent of the maturation stimulus but strictly dependent on PGE 2 on both monocytederived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE 2 -matured MoDCs showed enhanced costimulatory capacities resulting in augmented antigenspecific CD4 ؉ and CD8 ؉ T-cell prolifera- IntroductionDendritic cells (DCs) are key players in the defense against pathogens because of their unique capacity to induce primary and secondary T-cell responses. By presenting specific antigens on major histocompatibility complex and by expressing costimulatory molecules, DCs provide essential signals for optimal T-cell activation, prevention of tolerance, and development of T-cell immunity. The most important costimulatory receptor for early proliferation of naive T cells is CD28, which interacts with CD80 or CD86 on DCs. 1 However, CD28-CD80/86 costimulatory interactions cannot fully account for an efficient long-lasting T-cell response or the generation of memory T cells. 2 T-cell proliferation and survival at later phases and the development of memory T cells depend on additional costimulatory molecules belonging to the tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily and include OX40L/OX40, 4-1BBL/4-1BB, and CD70/CD27. 3 OX40 is induced on activated T cells and provides an essential signal for optimal CD4 ϩ T-cell function 4-7 as well as for the generation of memory T cells [8][9][10] by prolonging the survival of effector T cells. 9 Signaling through OX40 is controlled in vivo by the availability of its ligand OX40L. The expression of OX40L is tightly regulated and can be induced on antigen-presenting cells (APCs), such as DCs 11,12 and B cells 13 and microglia. 14 The lack of OX40L on APCs results in a marked reduction of cytokine production and proliferation of T-helper cells. 5,7 Murine DCs transfected with mRNA encoding OX40L induce enhanced antitumor activity in vivo, whereas transfection of OX40L mRNA in human monocyte-derived (Mo) DCs improves the induction of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro. 15 CD27 is expressed on naive CD4 ϩ and CD8 ϩ T cells 16 and on primed B cells, 17 and triggering of CD27 by CD70 supports T-cell survival. Consequently, constant activation of CD27 by persistent transgenic expression of CD70 on mouse B cells leads to excessive T-cell proliferation. 18,19 CD70 expression is transiently induced on T cells, B cells, a...

We demonstrate here that Fel d1-specific IgG antibodies interact with FcγRIIB which (i) promotes IgE internalization; and (ii) inhibits mast cell activation. These results broaden our understanding of allergen-specific desensitization and may provide a mechanism for long-term desensitization of mast cells by selective removal of long-lived IgE antibodies on mast cells.

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