title: Targeting of natural killer cells by rabbit antithymocyte globulin and campath-1H: similar effects independent of specificity.
abstract: T cell depleting strategies are an integral part of immunosuppressive regimens widely used in the hematological and solid organ transplant setting. Although it is known to induce lymphocytopenia, little is known about the effects of the polyclonal rabbit antithymocyte globulin (rATG) or the monoclonal anti-CD52 antibody alemtuzumab on Natural Killer (NK) cells in detail. Here, we demonstrate that induction therapy with rATG following kidney/pancreas transplantation results in a rapid depletion of NK cells. Treatment of NK cells with rATG and alemtuzumab in vitro leads to impairment of cytotoxicity and induction of apoptosis even at a 10-fold lower concentration (0.1 microg/ml) compared with T and B cells. By generating Fc-parts of rATG and alemtuzumab we illustrate that their ligation to FcgammaRIII (CD16) is sufficient for the significant induction of degranulation, apoptosis and inflammatory cytokine release (FasL, TNFalpha and IFNgamma) exclusively in CD3(-)CD56(dim) NK cells whereas application of rATG and alemtuzumab F(ab) fragments abolishes these effects. These findings are of general importance as our data suggest that NK cells are also mediators of the clinically relevant cytokine release syndrome and that their targeting by therapeutic antibodies should be considered as they are functionally relevant for the effective clearance of opportunistic viral infections and anti-tumor activity posttransplantation.
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Stauch
authors.forename: Annelie
authors.initials: A
authors.lastname: Dernier
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sarmiento Marchese
authors.forename: Kristina
authors.initials: K
authors.lastname: Kunert
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D017209:Apoptosis; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D011817:Rabbits; D017452:Receptors, IgG
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000961:Antilymphocyte Serum; D016207:Cytokines; D017452:Receptors, IgG; D000074323:Alemtuzumab