ABSTRACT
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.
Subject(s)
Immune System/drug effects , Immune System/radiation effects , Immunosuppressive Agents/pharmacology , Whole-Body Irradiation/methods , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , Cyclosporine/pharmacology , Cytokines/blood , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Dendritic Cells/radiation effects , Enzyme-Linked Immunosorbent Assay , Female , Homeostasis/drug effects , Homeostasis/radiation effects , Immune System/cytology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Leukocytes/drug effects , Leukocytes/metabolism , Leukocytes/radiation effects , Lymphocyte Count , Lymphocytes/drug effects , Lymphocytes/metabolism , Lymphocytes/radiation effects , Macaca mulatta/virology , Monocytes/drug effects , Monocytes/metabolism , Monocytes/radiation effects , Neutrophils/drug effects , Neutrophils/metabolism , Neutrophils/radiation effects , Tacrolimus/pharmacology , Varicellovirus/drug effects , Varicellovirus/growth & development , Varicellovirus/radiation effects , Viral Load/drug effects , Viral Load/radiation effects , Virus Activation/drug effects , Virus Activation/radiation effectsABSTRACT
We describe correlative clinicopathological/virological findings from a simian varicella virus (SVV)-seronegative monkey that developed disseminated varicella 105 days after gamma-irradiation. Twelve other monkeys in the colony were also irradiated, none of which developed varicella. Before irradiation, sera from the monkey that developed disseminated infection and one asymptomatic monkey were available. Analysis indicated that subclinical reactivation of latent SVV from an asymptomatic irradiated monkey likely led to disseminated varicella in the seronegative irradiated monkey. These findings parallel those from humans with disseminated varicella infection and support the usefulness of SVV infection as a model for human varicella-zoster virus infection, particularly virus reactivation after gamma-irradiation.