title: Simultaneous deletion of NOD1 and NOD2 inhibits in vitro alloresponses but does not prevent allograft rejection.
abstract: Pattern recognition receptors (PRRs) play an important role in host anti-donor responses to transplanted tissue. A key trigger of the host alloresponse involves recognition of foreign antigen presented on activated antigen presenting cells by the host T cells. Emerging data suggest that PRR blockade can abrogate host anti-donor responses by interfering with activation of antigen presenting cells, particularly activation of dendritic cells. Our study asked whether blockade of a well-characterized family of intracellular PRRs, the NOD family, interfered with alloantigen recognition and allograft rejection. We found that deletion of either NOD1 or NOD2 in antigen presenting cells (APCs) had no effect on induction of T cell proliferation to alloantigen, but that simultaneous deletion of NOD1 and NOD2 significantly inhibited T cell responses. There was however no effect of the NOD deletion on skin graft rejection when NOD1×NOD2 skin was transplanted onto allogeneic hosts or when WT skin was transplanted onto NOD1×NOD2 deficient recipients. The conclusion of this study is that in vitro alloresponses are negatively impacted by the simultaneous deletion of NOD1 and NOD2, but that allograft rejection across a stringent allo barrier is not affected. Our results suggest that the NOD family members, NOD1 and NOD2, play a collaborative role in T cell activation by alloantigen and that their blockade in vitro can inhibit T cell responses.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Sashi G
authors.initials: SG
authors.lastname: Kasimsetty
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Scheinok
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Alana A
authors.initials: AA
authors.lastname: Shigeoka
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States. Electronic address: d1mckay@ucsd.edu.
authors.forename: Dianne B
authors.initials: DB
authors.lastname: McKay
mesh_terms: D064591:Allografts; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D007519:Isoantigens; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4
keywords: Allograft rejection; Alloresponses; Innate immunity; NOD1; NOD2; Pattern recognition receptors