title: Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation.
abstract: Alemtuzumab (anti-CD52; Campath 1-H) depletes both host and donor T cells when used in preparative regimens for allogeneic transplantation. This promotes engraftment even after nonmyeloablative conditioning and limits graft-versus-host disease (GVHD) even after unrelated or major histocompatibility complex (MHC) disparate allografts. We asked whether anti-CD52 differentially targets antigen-presenting cells (APCs), in addition to depleting T cells. Monocyte-derived dendritic cells (moDCs) expressed abundant CD52 as expected. Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs), however, never expressed CD52. Immunostaining of skin and gut confirmed the absence of CD52 on these resident DC populations under both steady-state and inflammatory conditions. Although anti-CD52 functions primarily by antibody-dependent cellular cytotoxicity (ADCC) in vivo, assessment of its activity in vitro included complement-dependent lysis of CD52(+) cells. Anti-CD52 did not impair DC-T-cell adhesion, diminish DC-stimulated T-cell proliferation, or alter moDC development in vitro. We propose that anti-CD52 abrogates GVHD not only by T-cell depletion, but also by removing moDCs and their precursors. This would mitigate moDC phagocytosis and presentation of host-derived antigens to donor T cells in the inflammatory peritransplantation environment, thereby limiting GVHD. The sparing of LCs and DDC-IDCs by anti-CD52, as well as the recovery of donor-derived moDCs in a less inflammatory environment later after transplantation, may allow all these DCs to exert formative roles in graft-versus-tumor (GVT) reactions and immune reconstitution. Whether these results support a separation of deleterious from beneficial graft-host interactions at the level of antigen presentation, rather than solely at the level of T cells, will require further evaluation.
authors.affiliation: Laboratory of Cellular Immunobiology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ratzinger
authors.forename: John L
authors.initials: JL
authors.lastname: Reagan
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects*; D015703:Antigens, CD / Q000032:analysis* / Q000502:physiology; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000502:physiology; D000074301:CD52 Antigen; D002448:Cell Adhesion; D002455:Cell Division; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D006023:Glycoproteins / Q000032:analysis* / Q000502:physiology; D006086:Graft vs Host Disease / Q000517:prevention & control; D006087:Graft vs Host Reaction / Q000276:immunology*; D006098:Granulocytes / Q000276:immunology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000276:immunology; D006801:Humans; D007422:Intestines / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; C099444:9-(((ethoxyhydroxyphosphinyl)methoxy)methoxy)guanine; D000074323:Alemtuzumab; D006147:Guanine