Ablation of pathogenic memory T-cell responses by bone marrow-mediated gene therapy under immune-preserving conditions

Established memory T cell responses represent a key hurdle to both protein and tissue replacement therapies as well as the application of tolerogenic immunotherapies in general. Targeting expression of antigen to antigen-presenting cells is a powerful means to induce T-cell tolerance. We have shown previously that genetic targeting of antigens to DC and other APC inactivates memory CD4+ andCD8+ T cells, but we now show this can be exploited for induction of therapeutic tolerance to 'turn-off' established but unwanted T-cell responses. We have combine the approaches of targeted antigen expression and bone marrow (BM) / hematopoietic stem cell transplantation under immune-preserving conditions to show antigen-specific, therapeutic termination of memory CD4+ and CD8+ T-cell responses. This approach has the capacity to turn off the pathogenic T-cell responses that underlie autoimmune rejection of antigen-expressing pancreatic islet transplants and Th2-mediated airwaysinflammation. Associated with this immune-related pathology related to these responses, such asairways inflammation and hyper-responsiveness is prevented or ameliorated. Immunologicalmechanisms associated with reversal of established memory T-cell responses by BM transfer underimmune preserving conditions appear to be deletion and induction of unresponsiveness through T-cell'adaption'. Refinement of BM-mediated gene therapy for tolerance such as this could lead todevelopment of highly-effective therapies for T-cell mediated pathologies.