Research Article: Down Regulation of Genes Involved in T Cell Polarity and Motility during the Induction of Heart Allograft Tolerance by Allochimeric MHC I

Date Published: December 2, 2009

Publisher: Public Library of Science

Author(s): Wojciech Lisik, Neelam Tejpal, Yongquan Gong, T. Spencer Skelton, Malathesh Ganachari, Eric G. Bremer, Malgorzata Kloc, Rafik M. Ghobrial, Derya Unutmaz.

Abstract: The allochimeric MHC class I molecule [α1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells.

Partial Text: Transplantation of genetically incongruous organ generates the immune response, which may eventually result in the destruction of the grafted tissue [1], [2]. Because currently used immunosuppressants induce impairment of the recipient’s immune system, a major goal in transplantation is to prevent rejection by inducing tolerance while avoiding global immunosuppression [3], [4].

Our study of T cell expression profile showed that the expression levels of many genes either directly or indirectly involved in the molecular pathways responsible for T cell polarization, movement, scanning ability and the formation of the immunological synapse are down regulated during CsA + allochimeric molecule treatment when compared to CsA treatment alone or to the untreated control. The generation of immune response requires several highly specialized molecular and cellular events, which take place in sequential manner. First there is a migration of T cells toward the antigen presenting cells (APCs), followed by an initial adhesive contact between T cell and APC which allows for the scanning of APC surface by T cell, and finally the formation of the immunological synapse i. e. the close apposition of T cell and APC membranes necessary for the interaction between the T cell receptors (TCR) and major histocompatibility complex (MHC). The supramolecular spatial organization and highly dynamic clustering of the molecules in the immunological synapse allows T cell receptors to response to the antigen and to facilitate polarized secretion of cytotoxic granules and cytokines. All these events involve highly orchestrated polarization and rearrangements of cytoskeleton, membranes, vacuolar/endosomal compartments and cell adhesion and signaling molecules [14]–[21], [23], [25].



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