title: Dose and timing of interleukin (IL)-12 and timing and type of total-body irradiation: effects on graft-vs.-host disease inhibition and toxicity of exogenous IL-12 in murine bone marrow transplant recipients.
abstract: Paradoxically, a single injection of recombinant murine interleukin (IL)-12 on the day of bone marrow transplantation (BMT) inhibits graft-vs.-host disease (GVHD) while preserving graft-vs.-leukemia (GVL) effects in lethally irradiated mice receiving fully MHC-mismatched bone marrow and spleen cells. These protective effects are mediated by interferon (IFN)-gamma, whose early secretion is induced by IL-12 treatment. We investigated the relationship of IL-12 dose and timing of administration, as well as timing and type of total-body irradiation (TBI), with the ability of IL-12 to inhibit GVHD or mediate toxicity. The results show that a relatively low dose of IL-12 (as little as 50 U in a single injection) can mediate significant GVHD protection. The timing of IL-12 administration, however, is a critical factor. IL-12 administered 1 hour before BMT was most protective, but protection was still observed when it was administered 1-12 hours after BMT. Delaying IL-12 administration to 36 hours post-BMT completely obviated its protective effect. Administration of a second IL-12 injection 6 days after BMT negated the protective effect of an initial injection at the time of BMT. While IL-12 protection was evident when TBI was administered by 137Cs-irradiator in one or two fractions on day -1 or day 0, the use of an X-irradiator to deliver TBI on day -1 was associated with marked IL-12 toxicity. Whereas the protective effect of IL-12 against GVHD depended on donor-derived IFN-gamma, toxicity depended on the ability of host cells to produce IFN-gamma. Careful studies are warranted to test the effects of IL-12 in the context of BMT with various conditioning regimens in large animal preclinical models before this novel approach to GVHD protection can be applied clinically.
authors.affiliation: Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA. sykes@helix.mgh.harvard.edu
authors.forename: M
authors.initials: M
authors.lastname: Sykes
authors.forename: D A
authors.initials: DA
authors.lastname: Pearson
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
authors.forename: G L
authors.initials: GL
authors.lastname: Szot
authors.forename: S J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods; D002588:Cesium Radioisotopes / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control / Q000532:radiotherapy; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000379:methods*
chemical_list: D002588:Cesium Radioisotopes; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma