Abstracts Category : Other

Immune modulation by intravenous immune globulin: cross-talk between Fc gamma receptors and regulatory T cells in allergic inflammation

by Gabriel Kaufman

Intravenous immune globulin (IVIg), a preparation of pooled human antibodies, has potent immunomodulatory properties as a treatment for inflammatory pathologies. The specific mechanisms of action are not completely understood, especially in the context of allergen-driven disease. We sought to characterize several facets of IVIg regulatory biology using an established murine model of allergic airways disease. We first examined the requirement for activating and inhibitory Fc gamma receptors for the anti-inflammatory actions of IVIg, concluding that the inhibitory Fc gamma receptor IIb expression on dendritic cells is necessary and sufficient for IVIg to tolerize the immune system.Turning to the efferent end of the regulatory response, we studied the regulatory T cell compartment by selective depletion using cell-specific transgenic deletion mice. We demonstrated the absolute requirement for regulatory T cells in the IVIg-mediated anti-inflammatory response, and that IVIg generates a specific pool of regulatory T cells de novo from non-regulatory T cell precursors. We also characterized the gene expression profile of these IVIg-generated peripheral regulatory T cells, determining that they have a unique gene expression signature.In related work, we investigated the gene expression of activated B cells in a simulated regulatory context in vitro, profiling the transcriptome and reporting a novel marker for memory B cells that appears to play a role in B cell regulatory function.We complete this thesis with pertinent literature-review manuscripts and a supplemental review chapter on the roles of dendritic cells as activators of T cells. L'immunoglobuline intraveineuse (IgIV), une prparation d'anticorps humains, possde des proprits immunomodulatrices qui sont utilises comme traitement pour les pathologies inflammatoires. Les mcanismes spcifiques de son action ne sont pas entirement connus, spcialement dans le contexte des pathologies contrles par des antignes. Nous avons caractris plusieurs aspects de la biologie rgulatrice d'IgIV en utilisant un modle murin tabli de pathologie des voies ariennes. Nous avons premirement examin les conditions d'activation des rcepteurs Fc gamma activateurs et inhibiteurs des actions anti-inflammatoires d'IgIV, en concluant que l'expression du rcepteur inhibiteur Fc gamma IIb est ncessaire et suffisante pour que l'IgIV rende le systme immunitaire tolrant.Se concentrant sur le ct effrent de la rponse rgulatrice, nous avons tudi le compartiment des cellules T rgulatrices par dpltion cible, en utilisant des souris transgniques de suppression cellulaire. Nous avons dmontr le besoin absolu de la prsence de cellules T rgulatrices dans la rponse anti-inflammatoire mdie par l'IgIV, et que l'IgIV gnre une population spcifique de cellules T rgulatrices de novo partir de cellules prcurseures non-rgulatrices. Nous avons aussi caractris le profil d'expression gnique de ces cellules T rgulatrices priphriques gnres par l'IgIV, dmontrantAdvisors/Committee Members: Bruce Mazer (Supervisor).