Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency.
Human severe combined immunodeficiency (SCID) can be caused by defects in Janus kinase 3 (JAK3)-dependent cytokine signaling pathways. As a result, patients are at high risk of life-threatening infection. A JAK3 -/- SCID mouse model for the human disease has been used to test whether transplant with retrovirally transduced bone marrow (BM) cells (JAK3 BMT) could restore immunity to an influenza A virus. The immune responses also were compared directly with those for mice transplanted with wild-type BM (+/+ BMT). After infection, approximately 90% of the JAK3 BMT or +/+ BMT mice survived, whereas all of the JAK3 -/- mice died within 29 days. Normal levels of influenza-specific IgG were present in plasma from JAK3 BMT mice at 14 days after respiratory challenge, indicating restoration of B cell function. Influenza-specific CD4(+) and CD8(+) T cells were detected in the spleen and lymph nodes, and virus-specific CD8(+) effectors localized to the lungs of the JAK3 BMT mice. The kinetics of the specific host response correlated with complete clearance of the virus within 2 weeks of the initial exposure. By contrast, the JAK3 -/- mice did not show any evidence of viral immunity and were unable to control this viral pneumonia. Retroviral-mediated JAK3 gene transfer thus restores diverse aspects of cellular and humoral immunity and has obvious potential for human autologous BMT.
Bunting
K D
KD
Division of Experimental Hematology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Flynn
K J
KJ
Riberdy
J M
JM
Doherty
P C
PC
Sorrentino
B P
BP
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D007111:Immunity, Cellular; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D053616:Janus Kinase 3; D051379:Mice; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D014170:Transformation, Genetic
D000914:Antibodies, Viral; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3