Careful regulation of the bodys immunoglobulin G (IgG) and albumin concentrations

Careful regulation of the bodys immunoglobulin G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. adult life. The increasing appreciation for FcRn in both homeostatic and pathological conditions is generating an intense interest in the potential for therapeutic modulation of FcRn binding to IgG and albumin. infection [47]. Only when FcRn is expressed in the epithelium and in the presence of at these sites [42, 46, 53]. In a similar manner, the application of IgG-antigen complexes to the mucosal surfaces of the lung can promote an antigen-specific immune response consistent with the prediction that FcRn-mediated transport processes have the potential for being applied PF 477736 to vaccination strategies [54]. FcRn Functions in IgG and Albumin Protection From Catabolism Consistent with previous predictions PF 477736 by Brambell more than 40 years ago, FcRn is now known to be the factor responsible for the long half-life of IgG and albumin [11, 26, 27, 55C57]. In this process, FcRn has been shown in in vitro model systems to internalize these macromolecules by fluid phase endocytosis into an acidified endosome wherein FcRn can bind IgG and protect it from degradation by trafficking IgG PF 477736 (and albumin) PF 477736 away from a degradative fate in lysosomes and recycling them to the cell surface [26, 58C60]. As such, IgG and albumin possess half-lives of 21 and 16 days, respectively, in humans. Proof of these processes has come from studies in mice genetically deficient in FcRn expression wherein both hypogammaglobulinemia and hypoalbuminemia are observed, with a commensurate decrease in serum half-life for each of these molecules [11, 26, 27, 55C57]. Although parenchymal cells such as the endothelium likely play a significant role in IgG protectionas shown by conditional deletion of FcRn in this cell type in vivo [61]it is now clear that a significant fraction of IgG protection is due to the activities of hematopoietic cells. This is shown by studies using bone marrow chimeras with FcRn-deficient and FcRn-sufficient cells [55, 62]. The latter is consistent with the functional expression of FcRn in a wide variety of hematopoetic cell types in mouse and human, as discussed above. These observations have important therapeutic implications. Specifically, they raise the possibility that engineering IgG molecules with enhanced FcRn binding can increase IgG half-life and thus improve the pharmacokinetic and pharmacodynamic properties PF 477736 of therapeutic antibodies [as reviewed in detail by Presta [63] and Kuo [64]], Fc fusion proteins, and potentially albumin-based fusion proteins. This has indeed been accomplished, as discussed below, through the generation of monomeric Fc fusion proteins. On the other hand, blockade of FcRn binding of IgG potentially enables the degradation of pathogenic antibodies. This can be accomplished by administration of intravenous immunoglobulins (IVIG), which work in part through this mechanism by saturating FcRn with irrelevant antibodies [65C68]. Alternatively, antibodies and peptides have been developed that can block FcRn-IgG interactions and increase IgG catabolism [69C72]. Such approaches have been effective, with demonstrable activity in autoimmune and IgG mediated disease models [65, 67, 68, 73, 74]. FcRn Functions in Antigen Presentation by Professional Antigen-Presenting Cells The expression of FcRn in professional antigen-presenting cells (APC) has prompted an investigation of the role that FcRn plays not only in the UBCEP80 protection of IgG from catabolism, but also in antigen presentation. As such, it has been demonstrated that FcRn in mouse and human dendritic cells regulates MHC class II-restricted antigen presentation of model antigens such as ovalbumin, in the case of mouse, and human antigens such as gliadin, which is associated with celiac sprue [59, 75]. Dendritic cells that are deficient in FcRn, or that are provided with IgG-containing immune complexes unable to bind FcRn through site-directed mutagenesis of the FcRn binding sites.