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Immune Cell Reconstitution After Exposure to Potentially Lethal Doses of Radiation in the Nonhuman Primate

MacVittie, Thomas J.*; Bennett, Alexander W.*; V. Cohen, Melanie; Farese, Ann M.*; Higgins, Adam; Hankey, Kim G.*

doi: 10.1097/HP.0b013e3182a2a9b2
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Delayed immune reconstitution remains a major cause of morbidity associated with myelosuppression induced by cytotoxic therapy or myeloablative conditioning for stem cell transplant, as well as potentially lethal doses of total- or partial-body irradiation. Restoration of a functional immune cell repertoire requires hematopoietic stem cell reconstitution for all immune cells and effective thymopoiesis for T cell recovery. There are no medical countermeasures available to mitigate damage consequent to high-dose, potentially lethal irradiation, and there are no well characterized large animal models of prolonged immunosuppression to assess efficacy of potential countermeasures. Herein, the authors describe a model of T and B cell reconstitution following lethal doses of partial-body irradiation with 5% bone marrow sparing that includes full exposure of the thymus. Rhesus macaques (n = 31 male, 5.5–11.3 kg body weight) were exposed to midline tissue doses of 9.0–12.0 Gy using 6 MV LINAC-derived photons at a dose rate of 0.80 Gy min−1, sparing approximately 5% of bone marrow (tibiae, ankles, and feet). All animals received medical management and were monitored for myeloid and lymphoid suppression and recovery through 180 d post-exposure. Myeloid recovery was assessed by neutrophil and platelet-related hematological parameters. Reconstitution of B and T cell subsets was assessed by flow cytometric immunophenotyping, and recent thymic emigrants were identified by RT-PCR of T cell receptor excision circles. Mortality was recorded through 180 d post-exposure. Acute myelo-suppression was characterized by severe neutropenia and thrombocytopenia, followed by recovery 30–60 d post-exposure. Total T (CD3+) and B (CD20+) cells were reduced significantly following exposure and exhibited differential recovery patterns post-exposure. Both CD4+ and CD8+ subsets of naïve T cells and total CD4+ T cell counts remained significantly lower than baseline through 180 d post-exposure. The failure of recent thymic emigrants and naïve T cell subsets to recover to normal baseline values reflects the severe radiation effects on the recovery of marrow-derived stem and early thymic progenitor cells, their mobilization and seeding of receptive thymic niches, and slow endogenous thymic regeneration.

*University of Maryland, School of Medicine, Dept. of Radiation Oncology, Baltimore, MD; †Integrated Research Facility, Frederick, MD; ‡Naval Medical Research Center, Silver Spring, MD.

The authors declare no conflicts of interest.

For correspondence contact: TJ MacVittie, University of Maryland, School of Medicine, Dept. of Radiation Oncology, Baltimore, MD, or email at tmacvittie@som.umaryland.edu.

(Manuscript accepted 26 June 2013)

© 2014 by the Health Physics Society