title: Association of Hematological Nadirs and Survival in a Nonhuman Primate Model of Hematopoietic Syndrome of Acute Radiation Syndrome.
abstract: Recombinant human interleukin-12 (rHuIL-12) mitigates the hematopoietic subsyndrome of acute radiation syndrome (HSARS) after total body irradiation (TBI) in a nonhuman primate (NHP) model of HSARS. The mechanism for this effect appears to involve multiple effects of rHuIL-12 on hematopoiesis. We conducted a meta-analysis to examine hematological nadirs and survival across our three NHP completed studies. Animals were irradiated (700 cGy) and treated with a single subcutaneous injection of vehicle (n = 64) or rHuIL-12 (50-500 ng/kg; n = 108) 24-25 h after irradiation, or with daily subcutaneous injections of granulocyte-colony stimulating factor (G-CSF; 10 μg/kg/day) for 18 days starting 24-25 h after exposure (n = 26). Blood samples were obtained at various time points up to day 60 after TBI. Lymphocytes, neutrophils and platelets were significantly lower in nonsurvivors than in survivors in the overall sample and in each treatment group (P < 0.001 for each comparison, Wilcoxon rank-sum test). Lymphocyte nadir was the strongest and most consistent predictor of death by Spearman's rank correlation. Receiver operating characteristic (ROC) curve analysis of death and threshold hematologic nadir values (where nadir values less than or equal the threshold are predictive of death) showed that a threshold of 0.08 × 10(9)/L for lymphocytes had the largest positive predictive value of death (97.2% and 92.5% for the control and rHuIL-12 groups, respectively) and high sensitivity (76.1% and 62.7%, respectively), consistent with human radiation victims data. The current findings suggest that enhanced early bone marrow regeneration resulting in increases in nadir values for all major blood cell types may be the main mechanism of action by which rHuIL-12 mitigates the lethality of HSARS.
authors.affiliation: Neumedicines Inc., Pasadena, California.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Gluzman-Poltorak
authors.affiliation: Neumedicines Inc., Pasadena, California.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vainstein
authors.affiliation: Neumedicines Inc., Pasadena, California.
authors.forename: Lena A
authors.initials: LA
authors.lastname: Basile
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001792:Blood Platelets / Q000528:radiation effects; D001853:Bone Marrow / Q000528:radiation effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D018664:Interleukin-12 / Q000008:administration & dosage*; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D011323:Primates; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage*; D014916:Whole-Body Irradiation
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12