title: Combinations of anti-LFA-1, everolimus, anti-CD40 ligand, and allogeneic bone marrow induce central transplantation tolerance through hemopoietic chimerism, including protection from chronic heart allograft rejection.
abstract: Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vbeta11(+) T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening ("chronic rejection").
authors.affiliation: Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research, Basel, Switzerland. Barbara.Metzler@pharma.novartis.com
authors.forename: Barbara
authors.initials: B
authors.lastname: Metzler
authors.forename: Patrick
authors.initials: P
authors.lastname: Gfeller
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.forename: Grazyna
authors.initials: G
authors.lastname: Wieczorek
authors.forename: Christoph
authors.initials: C
authors.lastname: Heusser
authors.forename: Philip
authors.initials: P
authors.lastname: Lake
authors.forename: Andreas
authors.initials: A
authors.lastname: Katopodis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D004359:Drug Therapy, Combination; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006410:Hematopoiesis / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology; D013045:Species Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D007518:Isoantibodies; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand