title: Anti-LFA-1 or rapamycin overcome costimulation blockade-resistant rejection in sensitized bone marrow recipients.
abstract: While costimulation blockade-based mixed chimerism protocols work well for inducing tolerance in rodents, translation to preclinical large animal/nonhuman primate models has been less successful. One recognized cause for these difficulties is the high frequency of alloreactive memory T cells (Tmem) found in the (pre)clinical setting as opposed to laboratory mice. In the present study, we therefore developed a murine bone marrow transplantation (BMT) model employing recipients harboring polyclonal donor-reactive Tmem without concomitant humoral sensitization. This model was then used to identify strategies to overcome this additional immune barrier. We found that B6 recipients that were enriched with 3 × 10(7)  T cells isolated from B6 mice that had been previously grafted with Balb/c skin, rejected Balb/c BM despite costimulation blockade with anti-CD40L and CTLA4Ig (while recipients not enriched developed chimerism). Adjunctive short-term treatment of sensitized BMT recipients with rapamycin or anti-LFA-1 mAb was demonstrated to be effective in controlling Tmem in this model, leading to long-term mixed chimerism and donor-specific tolerance. Thus, rapamycin and anti-LFA-1 mAb are effective in overcoming the potent barrier that donor-reactive Tmem pose to the induction of mixed chimerism and tolerance despite costimulation blockade.
authors.affiliation: Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Haley
authors.initials: H
authors.lastname: Ramsey
authors.forename: Nina
authors.initials: N
authors.lastname: Pilat
authors.forename: Karin
authors.initials: K
authors.lastname: Hock
authors.forename: Christoph
authors.initials: C
authors.lastname: Klaus
authors.forename: Lukas
authors.initials: L
authors.lastname: Unger
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baranyi
authors.forename: Martina
authors.initials: M
authors.lastname: Gattringer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwaiger
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D046528:Chimerism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection; D007371:Interferon-gamma / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000627:therapeutic use*; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000166:cytology; D023001:Transplantation Tolerance
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D016169:Lymphocyte Function-Associated Antigen-1; C114320:anti-LFA-1 monoclonal antibody; D023201:CD40 Ligand; D007371:Interferon-gamma; D020123:Sirolimus