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Immune responses to products of viral vectors have posed formidable barriers to efficient gene therapies. The important immune effectors of the immune response include CD4+ T helper cells, CD8+ cytotoxic T cells, which are responsible for mediating elimination of transgene expression and B cells which produce neutralizing antibodies that block effective readministration of vector. In addition immune responses directed to neoantigens expressed by the transgene in vector-transduced cells, are also responsible for the rapid elimination of transgene expression. The Immunology Group is responsible for performing various assays to evaluate both cell mediated- as well as humoral immune responses in animal models of gene therapies. In this respect, the Group has undertaken analyses of immune responses in pre-clinical trials in gene therapy in mice, rats, rhesus monkeys, and dogs and in several clinical trials. These assays monitor adenovirus-, adeno-associated virus- and transgene-induced cell mediated and humoral immune responses.
The following schematic illustrates the various immunological processes for which the Immunology Group has developed methodologies:
Figure Legend: Antigen taken by antigen presenting cells (APC) is processed and presented by MHC class I to CD8 T cells , and MHC class II to CD4 T cells . Recognition of the antigen, along with costimulatory molecules (B7-CD28; CD40-CD40 ligand) results in activation of antigen-specific CD4 T cells, which leads to lymphoproliferation and cytokine secretion . Depending on several conditions (e.g. strength of antigen signaling, costimulation, cytokines secreted by APC, etc.) CD4 T cells differentiate into either TH1 or TH2 type cells. TH1 cells secrete predominantly IFNg (interferon-gamma), which plays a role in activation of cell mediated immune responses which culminates in activation of cytotoxic T lymphocytes . CTL have been shown to be responsible for elimination of transduced cells in vivo by effector mechanisms involving Fas-FasL and perforin-granzymes. TH2 cells on the other hand secrete IL-4, which helps B cells differentiate into antibody secreting plasma cells. Secretion of neutralizing antibodies results in blocking of vector readministration. The nature of the neutralizing antibody response can be measured by determining the antigen (by Western blot ) and isotype of the immunoglobulin.
Understanding the molecular mechanisms involved in the cascade of events from antigen uptake by antigen presenting cells to differentiation of T and B cells, will allow development of therapeutic immunosuppressive agents to allow persistent transgene expression and ability to readminister viral vectors.