Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques
C. Meyer
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Search for more papers by this authorJ. Walker
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorJ. Dewane
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Search for more papers by this authorF. Engelmann
Division of Biomedical Sciences, University of California–Riverside, Riverside, CA, USA
Search for more papers by this authorW. Laub
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorS. Pillai
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorCharles. R. Thomas Jr
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorCorresponding Author
I. Messaoudi
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Division of Biomedical Sciences, University of California–Riverside, Riverside, CA, USA
Correspondence: I. Messaoudi, University of California–Riverside, School of Medicine, 900 University Avenue, Riverside, CA 92521, USA. E-mail: [email protected]Search for more papers by this authorC. Meyer
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Search for more papers by this authorJ. Walker
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorJ. Dewane
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Search for more papers by this authorF. Engelmann
Division of Biomedical Sciences, University of California–Riverside, Riverside, CA, USA
Search for more papers by this authorW. Laub
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorS. Pillai
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorCharles. R. Thomas Jr
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Search for more papers by this authorCorresponding Author
I. Messaoudi
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR, USA
Division of Biomedical Sciences, University of California–Riverside, Riverside, CA, USA
Correspondence: I. Messaoudi, University of California–Riverside, School of Medicine, 900 University Avenue, Riverside, CA 92521, USA. E-mail: [email protected]Search for more papers by this authorSummary
In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher's Web site:
| Filename | Description |
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| cei12646-sup-0001-suppinfo01.eps318.2 KB |
Fig. S1. Simian varicella virus (SVV) infection, viral load and immunoglobulin (Ig)G titre. All animals in (a) cohort 1, (b) cohort 2 and (c) cohort 3 were infected intrabronchially with SVV at day 0. SVV DNA viral load was measured in whole blood (closed square) and bronchoalveolar lavage cells (BAL, open circle) by quantitative polymerase chain reaction (PCR) using primers and probe specific for SVV ORF21. Average copy number per 100 ng of DNA. (b) SVV-specific IgG antibody end-point titres were measured by standard enzyme-linked immunosorbent assay (ELISA) in (b) cohort 1 (open triangle), (d) cohort 2 (closed triangle) and (f) cohort 3 (closed square) rhesus macaques (RMs). Average ± standard error of the mean (s.e.m.). Solid line indicates limit of detection. Dashed line indicates onset or change in immunosuppressive treatment; total body irradiation (TBI), cyclosporin A (CsA), tacrolimus (TAC), prednisone (pred), anti-thymocyte globulin (ATG), anti-CD3 immunotoxin (CD3-IT) and Janus activated kinase inhibitor (JAK-Inh). |
| cei12646-sup-0002-suppinfo02.eps337.5 KB |
Fig. 2. The effect of immunosuppression on multiple factors in the plasma. Levels of chemokines, cytokines and growth factors in plasma were determined using multiplex technology in individual rhesus macaques (RMs) from (a) cohort 1, (b) cohort 2 and (c) cohort 3. Dashed line indicates onset or change in immunosuppressive treatment; total body irradiation (TBI), cyclosporin A (CsA), tacrolimus (TAC), prednisone (pred), anti-thymocyte globulin (ATG), anti-CD3 immunotoxin (CD3-IT) and Janus activated kinase inhibitor (JAK-Inh). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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