title: Enhancement of monoclonal antibody dependent cell mediated cytotoxicity by IL2 and GM-CSF.
abstract: Rodent monoclonal antibodies (MAb) directed against cells of the immune system may be used in vivo for applications including conditioning prior to marrow transplantation and treatment of lymphoid malignancies. Although some MAb may lyse targets by complement fixation, MAb dependent cell mediated cytotoxicity (MAb-DCC) appears to be an important additional effector mechanism. We have investigated the cellular basis of the phenomenon and the response of the effector cells to recombinant cytokines in an attempt to maximize the efficacy of MAb-DCC and thereby increase the therapeutic potency of MAbs. Blood mononuclear cells (PBM) coated with CAMPATH 1G (pan lymphocyte reactive rat IgG2b) MAb were used as targets (T) and autologous lymphocytes or granulocytes were used as effector (E) cells. We studied function in normal donors as well as patients 1 week before and 3-6 weeks after bone marrow transplantation (BMT). In the absence of CAMPATH 1G, specific 51Cr release from autologous PBM was less than 1% in all groups, even after pre-incubation of the effector cells with granulocyte-macrophage, colony stimulating factor (GM-CSF) or interleukin-2 (IL2). In the presence of 5 micrograms/ml of MAb, and at an E:T ratio of 50:1, lymphocytes from normal donors induced a low level (6.5%) of 51Cr release from auto PBM rising to 9% after pre-incubation of effector cells with IL2 (P = 0.02). Granulocytes had greater activity inducing 10% 51CR release (range 2-23%) which rose to 21.6% with GM-CSF (range 12-48%) (P less than 0.001). Pre-BMT, killing by lymphocytes and granulocytes was not significantly different from normal, and responded to IL2 and GM-CSF. In contrast, granulocyte killing after BMT was significantly impaired (51Cr release 3%) and showed no rise with GM-CSF. Killing by lymphocytes, however, remained normal, as did their IL2 response. Loss of granulocyte mediated MAb-DCC coincided with significant post-BMT impairment of oxidative metabolism; expression of Fc receptors II and III, however, was normal. Optimum therapeutic effect of MAb-DCC is likely to be achieved when MAb are given together with appropriate cytokines, the choice of which will depend upon the clinical circumstances.
authors.affiliation: Department of Haematology, Royal Free Hospital, Hampstead, London.
authors.forename: A C
authors.initials: AC
authors.lastname: Bianchi
authors.forename: H E
authors.initials: HE
authors.lastname: Heslop
authors.forename: P
authors.initials: P
authors.lastname: Veys
authors.forename: M
authors.initials: M
authors.lastname: Macey
authors.forename: M
authors.initials: M
authors.lastname: Holland
authors.forename: H G
authors.initials: HG
authors.lastname: Prentice
authors.forename: M K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D003115:Colony-Stimulating Factors / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006098:Granulocytes / Q000276:immunology; D006133:Growth Substances / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007376:Interleukin-2; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor