The Efficacy of Recombinant Thrombopoietin in Murine and Nonhuman Primate Models for Radiation‐Induced Myelosuppression and Stem Cell Transplantation

Abstract

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mplmediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed.

EPO-mediated expansion of late-stage erythroid progenitors in the bone marrow initiates recovery from sublethal radiation stress

“…52,53 In addition, animal studies indicate that cytokine therapies directed toward multipotential progenitors improve hematopoietic recovery after radiation injury and suggest that combination cytokine therapies may be most effective in treatment of radiation-induced cytopenias. [54][55][56] EPO therapy has also been shown to improve survival after lethal radiation exposure 23 and our data indicate that exogenous EPO can accelerate recovery of the erythron. These data raise the possibility that EPO, in combination with other cytokines, may play a useful role in treatment of the acute hematopoietic syndrome after accidental or intentional radiation exposure.…”

Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis

“…11,[25][26][27][28] Virtually all primitive HSC that display marrow repopulating activity express on their surface the receptor for TPO-c-Mpl. 26 Studies in Spleen (SP) samples Figure 3 Effect of G-CSF, TPO and Flt-3L given s.c. for 10 consecutive days on cytokine production by splenocytes during EAE course.…”

Role of thrombocytopenia in radiation-induced mortality and review of therapeutic approaches targeting platelet regeneration after radiation exposure

“…This is not surprising given that GM-CSF operates at an earlier point during hematopoietic maturation than G-CSF, which acts on only on common myeloid progenitors. Findings with TPO are extremely encouraging from a mass casualty, operational standpoint, because in mice and NHPs, TPO, alone or in combination, appears to confer benefits even when administration is delayed even up to 24 h post-irradiation [83,95],, and in many studies detailed in the table, when given as a single dose.…”