Blood, 15 February 2001, Vol. 97, No. 4, pp. 833-833
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.
Richard K. Burt
Northwestern University Medical School
