ROLE OF E4 IN ELICITING CD4 T-CELL AND B-CELL RESPONSES TO ADENOVIRUSVECTORS DELIVERED TO MURINE AND NONHUMAN PRIMATE LUNGS

Adenovirus vectors delivered to lung are being considered in the treat ment of cystic fibrosis (CP). Vectors from which El has been deleted e licit T-and B-cell responses which confound their use in the treatment of chronic diseases such as CF, In this study, we directly compare th e biology of an adenovirus vector from which E1 has been deleted to th at of one from which E1 and E4 have been deleted, following intratrach eal instillation into mouse and nonhuman primate lung. Evaluation of t he El deletion vector in C57BL/6 mice demonstrated dose-dependent acti vation of both CD4 T cells (i.e., TH1 and TH2 subsets) and neutralizin g antibodies to viral capsid proteins. Deletion of E4 and E1 had littl e impact on the CD4 T-cell proliferative response and cytolytic activi ty of CD8 T cells against target cells expressing viral antigens. Anal ysis of T-cell subsets from mice exposed to the vector from which El a nd E4 had been deleted demonstrated preservation of TH1 responses,vith markedly diminished TH2 responses compared to the vector with the del etion of El, This effect was associated with reduced TH2-dependent imm unoglobulin isotypes and markedly diminished neutralizing antibodies. Similar results were obtained in nonhuman primates. These studies indi cate that the vector genotype can modify B-cell responses by different ial activation of TH1 subsets. Diminished humoral immunity, as was obs erved with the El and E4 deletion vectors in lung, is indeed desired i n applications of gene therapy where readministration of the vector is necessary.