Regulatory CD4+ T cells in allergic asthma.

Active suppression by regulatory T cells (T(regs)) appears to play a key role in the downregulation of T-cell responses to foreign antigens. Several subtypes of T(regs) have been described but their mechanisms of action remain unclear. Recent data demonstrate that the suppressive capacity of natural T(regs) could be associated with cytotoxicity due to the release of granzymes, which are capable of apoptosis induction in target effector T lymphocytes and in antigen-presenting cells, such as dendritic cells. The mechanism of such nonspecific T(regs) is discussed. Peptide immunotherapy is thought to induce regulatory cells capable of suppressing autoimmune and allergic diseases. We have recently optimized a vaccination strategy by which cytotoxic antigen-specific adaptive T(regs) can be elicited towards allergens involved in allergic asthma. Such a strategy could be of value in the treatment of allergic asthma.

In vivo neutralization of a C2 domain-specific human anti-Factor VIII inhibitor by an anti-idiotypic antibody.

Factor VIII (FVIII) administration elicits specific inhibitory antibodies (Abs) in about 25% of patients with hemophilia A. The majority of such Abs reacts with FVIII C2 domain. mAbBO2C11 is a high-affinity human monoclonal antibody (mAb) directed toward the C2 domain, which is representative of a major class of human FVIII inhibitors. Anti-idiotypic Abs were raised to mAbBO2C11 to establish their neutralizing potential toward inhibitors. One mouse anti-idiotypic mAb, mAb14C12, specifically prevented mAbBO2C11 binding to FVIII C2 domain and fully neutralized mAbBO2C11 functional inhibitory properties. Modeling of the 3-D conformation of mAb14C12 VH and alignment with the 3-D structure of the C2 domain showed putative 31 surface-exposed amino acid residues either identical or homologous to the C2 domain. These included one C2 phospholipid-binding site, Leu2251-Leu2252, but not Met2199-Phe2200. Forty putative contact residues with mAbBO2C11 were identified. mAb14C12 dose-dependently neutralized mAbBO2C11 inhibitory activity in mice with hemophilia A reconstituted with human recombinant FVIII (rFVIII), allowing full expression of FVIII activity. It also neutralized in an immunoprecipitation assay approximately 50% of polyclonal anti-C2 Abs obtained from 3 of 6 unrelated patients. mAb14C12 is the first example of an anti-idiotypic Ab that fully restores FVIII activity in vivo in the presence of an anti-C2 inhibitor. The present results establish the in vitro and in vivo proof of concept for idiotype-mediated neutralization of a major class of FVIII inhibitors.