Cyclosporin A reduces the inflammatory response to a multi-mutant herpes simplex virus type-1 leading to improved transgene expression in sympathetic preganglionic neurons in hamsters.
Herpes simplex virus type 1 (HSV-1) based vectors hold great promise for gene transfer to CNS neurons. Problems such as loss of transgene expression, vector-associated cytotoxicity and the immune response to the vector or encoded transgene still remain obstacles to success. We used a replication-defective, HSV-1 vector (14Hdelta3vhsZ) that was engineered to have reduced cytotoxicity and express recombinant beta-galactosidase. A previous study in our laboratory showed no evidence for cytotoxicity in infected neurons although an inflammatory infiltrate occurred around infected cells and transgene expression was lost between 5 and 8 days. The immune response consisted of a primary response at the site of inoculation (adrenal gland), and a secondary immune response in the spinal cord around infected adrenal sympathetic preganglionic neurons due to retrograde transport of the vector. We tested whether conventional immunosuppressants could reduce the secondary immune response, leading to improved transgene expression at the secondary CNS site. 14Hdelta3vhsZ was injected into the adrenal gland in hamsters 1 day after immunosuppressant treatment began. Non-drug treated, 14Hdelta3vhzZ-infected hamsters were used as controls. Cyclosporin A administration led to the most persistent beta-galactosidase activity in neurons at 5 and 8 days. Methylprednisolone treatment resulted in the greatest reduction in the inflammatory cell infiltrate but the numbers of infected neurons did not increase concomitantly. This suggested no direct relationship between extent of the inflammatory cell infiltrate and level of transgene expression. These data demonstrate the potential of cyclosporin A as an immunosuppressant adjunct treatment for HSV-1 vector-mediated gene transfer from a peripheral site to neurons in the spinal cord.
Neurodegeneration Research Group, The John P. Robarts Research Institute, London, Ontario, Canada.
P J
PJ
Mabon
L C
LC
Weaver
G A
GA
Dekaban
D000311:Adrenal Glands / Q000276:immunology / Q000821:virology*; D000818:Animals; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D003673:Defective Viruses / Q000235:genetics* / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology; D006651:Histocytochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D008775:Methylprednisolone / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D013997:Time Factors; D019076:Transgenes / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics; D001616:beta-Galactosidase / Q000032:analysis
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001616:beta-Galactosidase; D008775:Methylprednisolone