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T-cell response to xenografts and local immunosuppression.

Robyn Sutherland¹, Jamie Brady¹, Sarah Londrigan¹, Yifan Zhan¹, Wayne Hawthorne², Mark Nottle³, Philip O’Connell², Peter Cowan⁴, Anthony d’Apice⁴, Andrew Lew¹

¹Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; ²Westmead Millennium Institute, Sydney, Australia; ³University of Adelaide, Adelaide, Australia; ⁴St Vincent’s Hospital, Melbourne, Australia

Conventional immunosuppressive drugs are administered systemically predisposing the host to infections and cancer. Further, these drugs have off-target (non-immunological) effects that adversely affect the host as well as grafted tissues. Local delivery of immunosuppressive biologicals that specifically target immune cells is one strategy for reducing these side effects. Using a mouse allograft model, we have shown that islets that are genetically modified (by transgenesis or use of adenoviral transduction) so that they secrete anti-CD4 T cell-depleting antibody undergo reduced graft rejection. Our data indicates that the graft site is a critical site of action. T cell depletion at the graft site without systemic depletion confers graft protection. Furthermore, islets secreting T cell-depleting antibody are preferentially protected by comparison to control islets placed at a remote site within the same animal. We are currently pursuing the translation of these studies into a large animal model. We have produced an anti-CD2 monoclonal antibody that targets CD4 and CD8 T cells both of which contribute to xenograft rejection. The anti-CD2 antibody was selected for cross-reactivity on human and non-human primate CD2 with the premise that this cross-reactivity will enable testing in preclinical models with subsequent testing of the same antibody in clinical trials. The antibody inhibits an in vitro allogeneic mixed lymphocyte reaction and depletes human T cells in a humanized mouse model (hu-SCID). We have generated adenovirus encoding anti-CD2 (Adv-anti-CD2) and shown that this elicits efficient anti-CD2 antibody expression when used to transduce pig neonatal islet cell clusters (NICC). We are currently performing functional tests of anti-CD2 antibody secreted from Adv-anti-CD2 transduced NICC in the hu-SCID model as a prelude to testing in non-human primates.