Readministration of adenovirus vector in nonhuman primate lungs by blockade of CD40-CD40 ligand interactions

The interaction between CD40 on B cells and CD40 ligand (CD40L) on activate d T cells is important for B-cell differentiation in T-cell-dependent humor al responses. We have extended our previous murine studies of CD40-CD40L in adenoviral vector-mediated immune responses to rhesus monkeys. Primary imm une responses to adenoviral vectors and the ability to readminister vector were studied in rhesus monkeys in the presence or absence of a transient tr eatment with a humanized anti-CD40 ligand antibody (hu5C8). Adult animals w ere treated with hu5C8 at the time vector was instilled into the lung. Immu nological analyses demonstrated suppression of adenovirus-induced lymphopro liferation and cytokine responses (interleukin-2 [IL-2], gamma interferon, IL-4, and IL-10) in hu5C8-treated animals. Animals treated with hu5C8 secre ted adenovirus-specific immunoglobulin M (IgM) levels comparable to control animals, but did not secrete IgA or develop neutralizing antibodies; conse quently, the animals could be readministered with adenovirus vector express ing alkaline phosphatase. A second study was designed to examine the long-t erm effects on immune functions of a short course of hu5C8. Acute hu5C8 tre atment resulted in significant and prolonged inhibition of the adenovirus-s pecific humoral response well beyond the time hu5C8 effects were no longer significant. These studies demonstrate the potential of hu5C8 as an immunom odulatory regimen to enable administration of adenoviral vectors, and they advocate testing this model in humans.