title: Antagonistic effects of systemic interleukin 2 on immune Tcell-mediated graft-versus-leukemia reactivity.
abstract: This study demonstrates that systemic interleukin 2 (IL-2) can decrease the homing of syngeneic immune T cells to the target organ of metastases and accelerate unwanted side effects of allogeneic immune T cells. As a tumor system, we used the well-characterized highly aggressive DBA/2 mouse leukemia ESb and its less aggressive adhesion variant, ESb-MP. Systemic IL-2 treatment was performed with recombinant human interleukin-2 (Proleukin), which was slowly released via an implanted osmotic pump or was modified with polyethylene glycol (PEG-IL-2) to achieve constant plasma levels. Allogeneic B10.D2 antitumor immune spleen cells (ISPL cells) exerted strong graft-versus-leukemia (GvL) reactivity after adoptive transfer into late-stage ESb-MP tumor-bearing DBA/2 mice. Mls(a) superantigen-reactive vbeta6 donor T cells were not eliminated or tolerized by in vivo priming with the tumor cells and were present in active proliferation in liver infiltrates. When exogenous PEG-IL-2 or Proleukin was applied in addition to ISPL cells in such mice, the strong GvL-mediated protective immunity was converted into a fatal graft-versus-host disease. IL-2 treatment alone had no toxic effect and caused a moderate protection effect in the absence of an effect on local tumor growth. Potentiation of GvH reactivity of B10.D2 ISPL by PEG-IL-2 was proven in non-tumor-bearing DBA/2 mice, in which graft-versus-host disease was characterized by: (a) heavy hepatic lymphocytic infiltration, (b) irreversible increase of serum glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase levels, (c) weight loss, and (d) death. Antagonistic effects of systemic IL-2 on GvL were observed with syngeneic DBA/2 anti-ESb immune peritoneal effector cells (PECs). There was a detrimental effect of systemic IL-2 on liver target organ infiltration by immune T cells causing, at day 6 after transfer, a drop from 20-30 CD4 or CD8 T cells per liver lobule in the PEC group to <5 in the PEC plus IL-2 group. The results emphasize the importance of a better understanding of IL-2 function in vivo and of its interaction with immune cell function to improve protocols for optimal application in the clinic to achieve maximal GvL effects.
authors.affiliation: German Cancer Research Center, Division of Cellular Immunology, Heidelberg. V.Schirrmacher@dkfz-heidelberg.de
authors.forename: V
authors.initials: V
authors.lastname: Schirrmacher
authors.forename: S
authors.initials: S
authors.lastname: Müerköster
authors.forename: V
authors.initials: V
authors.lastname: Umansky
mesh_terms: D000818:Animals; D006087:Graft vs Host Reaction / Q000187:drug effects / Q000276:immunology; D020350:Graft vs Tumor Effect / Q000187:drug effects* / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects*; D007376:Interleukin-2 / Q000494:pharmacology*; D008111:Liver Function Tests; D051379:Mice; D008811:Mice, Inbred DBA; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007376:Interleukin-2