Immunomodulation and adenoviral gene transfer to the lungs of nonhuman primates

Previous data from our laboratory and others have demonstrated a critical r ole for the CD4(+) T lymphocyte in in vivo immune responses to recombinant adenoviral vectors. In rodent models, this subset of T cells is required fo r T cell proliferation, subsequent cytotoxic T cell generation, and product ion of anti-adenoviral antibodies by B cells. Both depleting and nondepleti ng anti-CD4 antibodies can attenuate these immune responses to recombinant adenovirus, On the basis of these data, we hypothesized that a nondepleting CDR-engrafted anti-human CD4 antibody (OKT4A) with cross-reactivity to rhe sus macaques would attenuate both T and B cell responses to intrapulmonary administration of recombinant adenovirus and permit prolonged reporter gene expression and permit secondary gene transfer. Juvenile rhesus macaques we re treated with PBS or OKT4A antibody (10 mg/kg) daily beginning 1 day prio r to and up to 11 days after gene transfer. OKT4A resulted in significant a ttenuation of lymphocyte recruitment into the lung, lymphocyte-proliferativ e responses to both adenovirus capsid proteins and transgene protein, and a denovirus-induced interferon-gamma elaboration in whole blood and hilar lym ph nodes. However, OKT4A was ineffective in attenuating adenovirus-induced IL-4 production in whole blood or hilar lymph nodes, generating neutralizin g anti-adenoviral antibodies, or permitting secondary gene transfer. As all the monkeys in this protocol had baseline-detectable anti-adenoviral antib odies by ELISA that were nonneutralizing, analogous to most patients with c ystic fibrosis, we postulate that anti-CD4 did not block the proliferation of memory B cells. Moreover, these data suggest that for transient immunomo dulation to be successful, strategies need to focus specifically on B cell activation independent of CD4(+) T cell help.