Gene therapy to re-establish self-tolerance

Chen et al (page 886) discuss a gene therapy approach for induction of tolerance. Tolerance is antigen-specific unresponsiveness with intact immunity to other third-party antigens. Tolerance may be achieved within the thymus by deletion (ie, apoptosis) of autoreactive clones. Because not all self-reactive T lymphocytes are eliminated in the thymus, peripheral (postthymic) tolerance is necessary to prevent autoimmunity. Peripheral T-cell tolerance arises when antigen-presenting cells (APCs) present an antigen without a costimulatory molecule (eg, B7-1, B7-2). Peripheral tolerance may be broken by immunization. Direct immunization induces disease by providing the self-peptide along with an adjuvant or immune stimulant that up-regulates costimulatory molecules on APCs. Immunization of animals with myelin peptide results in T-cell activation and initiates experimental autoimmune encephalomyelitis (EAE), a disease histologically and clinically similar to multiple sclerosis.

In the study by Chen et al, a retrovirus was used to genetically modify B cells to present myelin peptide. Because resting B cells do not present costimulatory molecules, T-cell tolerance was induced to the myelin epitope. If treatment occurs prior to disease onset, the number of affected animals and disease severity is decreased. Because treatment is not designed to suppress or eliminate T-cell clones that have already been activated against self-determinants, it remains unclear whether this approach would help ameliorate established disease. Therefore, although encouraging, this method is yet to be proven clinically practical.