Immune regulation of transgene expression in the brain: B cells regulate an early phase of elimination of transgene expression from adenoviral vectors.
Cellular immune mechanisms that regulate viral gene expression within infected brain cells remain poorly understood. Previous work has shown that systemic immunization against adenovirus after vector delivery to the brain results in complete loss of brain cells infected by adenoviral vectors. Although T cells play an important role in this process, we demonstrate herein that B cells also significantly regulate transgene expression from the CNS. After the systemic immunization against adenovirus of animals injected via the brain with an adenoviral vector 30 days earlier, we uncovered substantial infiltration by CD19+ B cells of the area of the brain transduced by the virus. This suggests the involvement of B cells in the adaptive immune response-mediated loss of transduced cells from the brain. Confocal analysis of these brains demonstrated physical contacts between transduced brain cells and CD19+ cells. To test the hypothesis that B cells play a causal role in the loss of infected cells from the brain, we demonstrated that animals devoid of B cells were unable to eliminate transgene expression at early time points after immunization. This demonstrates that B cells play a necessary role in the loss of transgene expression at early, but not late, time points postimmunization. Thus, these data have important implications for our understanding of the role of B cells as immune effectors during the immune-mediated clearance of viral infections from the CNS, and also for understanding mechanisms operating in brain autoimmunity, as well as for the potential safety of clinical gene therapy for brain diseases.
Zirger
Jeffrey M
JM
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA.
Liu
Chunyan
C
Barcia
Carlos
C
Castro
Maria G
MG
Lowenstein
Pedro R
PR
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000257:Adenoviridae Infections / Q000276:immunology* / Q000821:virology; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000821:virology*; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes / Q000502:physiology*
D018941:Antigens, CD19; D013937:Thymidine Kinase