Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes

Abstract

Lymphoid lineage recovery and involution after exposure to potentially lethal doses of ionizing radiation have not been well defined, especially the long-term effects in aged survivors and with regard to male / female differences. To examine these questions, male and female C57BL/6 mice were exposed to lethal radiation at 12 weeks of age in a model of the Hematopoietic-Acute Radiation Syndrome, and bone marrow, thymus, spleen and peripheral blood examined up to 24 months of age for the lymphopoietic Delayed Effects of Acute Radiation Exposure. Aged mice showed myeloid skewing and incomplete lymphocyte recovery in all lymphoid tissues. Spleen and peripheral blood both exhibited a mono-phasic recovery pattern while thymus demonstrated a biphasic pattern. Naïve T cells in blood and spleen and all subsets of thymocytes were decreased in aged irradiated mice compared to age-matched non-irradiated controls. Of interest, irradiated males experienced significantly improved reconstitution of thymocyte subsets and peripheral blood elements compared to females. Bone marrow from aged irradiated survivors was significantly deficient in the primitive lymphoid-primed multipotent progenitors and common lymphoid progenitors, which were only 8-10% of levels in aged-matched non-irradiated controls. Taken together, these analyses define significant age-and sex-related deficiencies at all levels of lymphopoiesis throughout the lifespan of survivors of the Hematopoietic-Acute Radiation Syndrome, and may provide a murine model suitable for assessing the efficacy of potential medical countermeasures and therapeutic strategies to alleviate the severe immune suppression that occurs after radiation exposure.

Modeling Cell Survival Fraction and Other Dose-Response Relationships for Immunodeficient C.B-17 SCID Mice Exposed to 320-kV X Rays

“…For a longer period before assessing cell survival, some repopulation of cells could occur. 32 Our view that successful bone marrow engraftment studies in mice could be achieved using 320-kV X rays is supported by results of others 4 who achieved successful bone marrow engraftment in male C57BL/6 mice whole-body exposed via an X-ray source irradiator (Rad Source 2000 X-ray Biologic Irradiator, Rad Source Technologies, Alpharetta, GA). They also achieved successful engraftment using 137 Cs g rays (Irradiator: Gamma Cell 40, MSD Nordion, Ottawa, Ontario, Canada).…”

“…Studies using small animal models of hematopoietic system cell survival after exposure to X rays or γ rays has been a practice for decades and are important for bone marrow transplantation, medical counter measures, and other study-protocol planning. 32 Previously we performed successful bone marrow transplantation in Cs-137 γ-ray, split-dose exposed (bilaterally) C.B-17 immunocompetent anesthetized mice 5 but not with now-considered “not comparable” effective doses (based on an updated RBE estimate) of 320-kV X rays from the same X-RAD 320 irradiator as used in our present studies. Based on careful consideration of the research data generated, we think the most likely reason for the lack of success for 320 kV X rays was due to the RBE estimate (RBE = 1.3) used in the study design being too large, leading to the absorbed doses used being too small.…”

“…The negative curvature dose-response relationships for S ck (D) and H ck (D) for both cell types can be explained on the basis of a mixture of cells with different radiosensitivity distributions for both spleen and bone marrow. [30][31][32] Interestingly, for spleen there is strong evidence for a hyper-radiosensitive subpopulation, where 50% of all cells are eliminated by a dose of approximately 0.5 Gy (500 mGy). This is not the case for bone marrow.…”

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

“…Hematopoietic DEARE, also known as residual bone marrow damage (RBMD), is characterized by diminished immunity and decreased production of blood cells persisting for years after radiation exposure [173][174][175][176][177][178][179]. Survivors of H-ARS exhibit severe lifelong damage to HSC, characterized by significantly decreased complete blood count, loss of HSC repopulating potential, loss of HSC quiescence, decreased numbers of HPC, and dramatic myeloid skewing, all most evident under stress [173][174][175][176][177][178][179][180][181][182][183].…”

“…Hematopoietic DEARE, also known as residual bone marrow damage (RBMD), is characterized by diminished immunity and decreased production of blood cells persisting for years after radiation exposure [173][174][175][176][177][178][179]. Survivors of H-ARS exhibit severe lifelong damage to HSC, characterized by significantly decreased complete blood count, loss of HSC repopulating potential, loss of HSC quiescence, decreased numbers of HPC, and dramatic myeloid skewing, all most evident under stress [173][174][175][176][177][178][179][180][181][182][183]. An increased incidence of lymphoid malignancies, shortened life span, decreased mesenchymal stem/progenitor cell (MSC) number, and aberrant levels of endothelial cell-derived HSC niche proteins in aged H-ARS survivors have also been documented (Orschell, unpublished data).…”