Indiana University-Purdue University Indianapolis (IUPUI) / There is an urgent demand for effective medical countermeasures (MCM) in the event of high-dose radiation exposure ranging from nuclear plant disasters to potential nuclear warfare. Victims of lethal-dose radiation exposure face multi-organ injuries including the hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE) years after irradiation. Defective lymphocyte reconstitution and its subsequent immune insufficiency are some of the most serious consequences of H-ARS and DEARE. In order to investigate potential MCMs to protect or mitigate these radiation injuries, the prolonged tissue-specific immunosuppression at all levels of lymphocyte development in established murine H-ARS and DEARE models was defined, along with unique sex-related and age-related changes present in some tissues but not others. The “double hits” of irradiation and age-related stress on lymphopoiesis led to significant myeloid skew and long-term immune involution. Different kinds and different combinations of hematopoietic growth factors, some in combination with angiotensin converting enzyme inhibitor, were administered to lethally irradiated mice. These radiomitigators were found to significantly increase survival and enhance hematopoiesis in H-ARS, but they did little to alleviate the severity of DEARE including immune insufficiency. 16,16 dimethyl-prostaglandin E2 (dmPGE2), a long-acting formulation of PGE2 with similar biological effects as PGE2, was found to enhance survival and hematopoiesis in lethal-irradiated mice when used as radiomitigator or radioprotectant. The optimum time window for administration of radioprotectant and radiomitigator dmPGE2 was defined, which is -3hr to -15min prior to irradiation and +6hr to +30hr post irradiation. Significant survival efficacy of radioprotectant dmPGE2 was also demonstrated in pediatric and geriatric mice. Using specific PGE2 receptor (EP) agonists, the EP4 receptor was defined as the PGE2 receptor potentially responsible for dmPGE2 radioprotection. Radioprotectant dmPGE2 was also found to prevent radiation-induced thymic involution and to ameliorate the long-term immune suppression in radiation survivors in the DEARE phase via promoting hematopoietic stem cell differentiation towards to the lymphoid lineage. This is the first report of an effective MCM for H-ARS which also targets long-term thymic involution and lymphoid lineage reconstitution.

Pour certaines maladies causées par des agents chimiques, biologiques, radiologiques et nucléaires (CBRN), il n’existe pas de contre-mesures médicales (MedCM) et bon nombre de celles qui existent pourraient ne pas être disponibles en cas de besoin. En cas d’accident CBRN, des efforts inadéquats de financement de la R&D et de mise à disposition par les gouvernements peuvent avoir de graves conséquences économiques nettement supérieures aux coûts d’initiatives préventives. Compte-tenu des contraintes budgétaires auxquelles de nombreux gouvernements sont confrontés, il est nécessaire de définir des priorités. Parallèlement à la mise en place d’indicateurs de décision de santé efficaces qui identifient et mesurent les effets de causalité de l’impact négatif sur la santé, le processus de décision doit également prendre en considération le rapport coût-efficacité pour rendre le financement durable.Cette thèse a pour objectif de définir une voie vers une politique économique de santé publique visant à renforcer la disponibilité des MedCM pour les agents CBRN. Dans la première partie, les causes des défaillances du marché sont identifiées (lorsque les opportunités de profit ne compensent pas l’effort de R&D nécessaire). Dans la deuxième partie, des études de cas illustrent les caractéristiques et les conséquences économiques d’exemples d’accidents CBRN et des scénarios sont analysés afin de mettre en évidence comment la disponibilité de MedCM pourrait potentiellement devenir rentable. Enfin, la troisième partie propose des approches plus complètes pour mesurer et compenser les facteurs contribuant à la défaillance du marché en appliquant des modèles économiques spécifiques. / For some diseases caused by chemical, biological, radiological, and nuclear (CBRN) agents, innovative medical countermeasures (MedCMs) do not exist while many of those that do might not be readily available. In case of a CBRN event, inappropriate medical research and development (R&D) funding and government procurement efforts can result in adverse economic consequences (e.g. lost income) far exceeding the costs of strong and comprehensive preparedness initiatives. Given the budgetary constraints many governments face, priorities must be defined. Parallel to determining effective health decision metrics that identify and weigh the causal effects of negative health impact, decision making must also consider cost-effectiveness to make funding sustainable. Moreover, international cooperation is necessary since the risks increasingly transcend borders due to global travel and the global threat of terrorism. This dissertation ultimately seeks to define a path to public health economic policy to enhance the international availability of CBRN MedCMs. In Part I, the root causes of market failure are identified and depicted (i.e., where rewards for supply do not adequately compensate for the R&D effort). In Part II, case study examples illustrate the characteristics and economic consequences of CBRN incidents. Scenarios for each case are outlined to show where the availability of MedCMs in these situations could potentially be cost-effective. Finally, Part III construes more comprehensive approaches for gauging and offsetting the deterrence factors of market supply and demand by compiling and applying additional economic models and frameworks.