Innate functions of immunoglobulin M lessen liver gene transfer with helper-dependent adenovirus.
The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naïve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naïve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors.
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Carmen
C
Unzu
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Ignacio
I
Melero
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Aizea
A
Morales-Kastresana
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Ana
A
Sampedro
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Irantzu
I
Serrano-Mendioroz
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Arantza
A
Azpilikueta
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
María Carmen
MC
Ochoa
Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.
Juan
J
Dubrot
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Eduardo
E
Martínez-Ansó
Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Antonio
A
Fontanellas
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002213:Capsid / Q000737:chemistry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000737:chemistry*; D008099:Liver / Q000166:cytology / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018398:Homeodomain Proteins; D007106:Immune Sera; D007075:Immunoglobulin M; C064658:RAG-1 protein