Hematological Changes as Prognostic Indicators of Survival: Similarities Between Gottingen Minipigs, Humans, and Other Large Animal Models

The animal efficacy rule addressing development of drugs for selected disease categories has pointed out the need to develop alternative large animal models. Based on this rule, the pathophysiology of the disease in the animal model must be well characterized and must reflect that in humans. So far, manifestations of the acute radiation syndrome (ARS) have been extensively studied only in two large animal models, the non-human primate (NHP) and the canine. We are evaluating the suitability of the minipig as an additional large animal model for development of radiation countermeasures. We have previously shown that the Gottingen minipig manifests hematopoietic ARS phases and symptoms similar to those observed in canines, NHPs, and humans.We establish here the LD50/30 dose (radiation dose at which 50% of the animals succumb within 30 days), and show that at this dose the time of nadir and the duration of cytopenia resemble those observed for NHP and canines, and mimic closely the kinetics of blood cell depletion and recovery in human patients with reversible hematopoietic damage (H3 category, METREPOL approach). No signs of GI damage in terms of diarrhea or shortening of villi were observed at doses up to 1.9 Gy. Platelet counts at days 10 and 14, number of days to reach critical platelet values, duration of thrombocytopenia, neutrophil stress response at 3 hours and count at 14 days, and CRP-to-platelet ratio were correlated with survival. The ratios between neutrophils, lymphocytes and platelets were significantly correlated with exposure to irradiation at different time intervals.As a non-rodent animal model, the minipig offers a useful alternative to NHP and canines, with attractive features including ARS resembling human ARS, cost, and regulatory acceptability. Use of the minipig may allow accelerated development of radiation countermeasures

Monitoring of erythropoiesis by the serum transferrin receptor and erythropoietin.

Virtually all cells have transferrin receptors (a transmembrane glycoprotein) on their surface but in a normal adult, 80% of them are in the erythroid marrow. Some of them are lost into the circulation where they can be measured by immuno-assays. A direct and highly significant correlation exists between serum transferrin receptor level and erythron transferrin uptake in humans. The measurement of serum transferrin receptor has wide clinical applications for the quantitation of erythropoiesis. It can be used to study erythropoiesis in situations in which ferrokinetics is not acceptable such as pregnancy. It is particularly useful for serial studies, e.i., for monitoring the recovery of erythropoiesis after stem cell transplantation or after treatment with erythropoietin. Combined with the determination of serum erythropoietin, both evaluated in relation to the degree of anemia, they provide a physiological approach to the diagnosis of anemia. Thus, the simultaneous determination of hematocrit, reticulocytes, serum transferrin receptor and serum erythropoietin has high discriminatory value in distinguishing between a defect in erythroid proliferation, maturation or red cell survival. It is also particularly useful for detecting the presence of multiple mechanisms of anemia in the same patient