Walter & Eliza Hall Institute of Medical Research
Anti-CD2 producing pig xenografts effect localized depletion of human T cells in a humanized mouse model
Jamie L Brady1,2, Robyn M Sutherland1,2, Manuela Hancock1, Susie Kitsoulis3, Mireille H Lahoud3,4, Peta M Phillips5, Wayne J Hawthorne5, Anthony J d'Apice6,7, Peter J Cowan6,7, Leonard C Harrison1,2, Philip J O'Connell5, Andrew M Lew1,2,8.
1Walter & Eliza Hall Insitiute of Medical Research, Parkville, Australia; 2Department of Medical Biology, The University of Melbourne, Parkville, Australia; 3Burnet Institute, Melbourne, Australia; 4Department of Immunology, Monash University, Melbourne, Australia; 5Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia; 6Department of Medicine, The University of Melbourne, Parkville, Australia; 7Immunology Research Centre, St Vincent's Hospital, Fitzroy, Australia; 8Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia
We investigated whether locally produced anti-human CD2 antibody (Ab), mediated by adenovirus (Adv) transduction of pig neonatal islet cell clusters (pNICCs), would protect xenografts in a humanized mouse model from immune attack and whether such immunosuppression would remain local. A mouse anti-human CD2 Ab (CD2hb11) previously generated by us was genetically engineered to produce chimeric and humanized versions. Both CD2hb11 and chimeric CD2hb11 inhibited proliferation of a xenogeneic MLR in a dose-dependent manner whereas humanized CD2hb11 did not. Chimeric CD2hb11 showed a 300-fold higher avidity than humanized CD2hb11. Administration of these Abs depleted T cells in a huSCID model, but did not induce upregulation of activation markers or significant release of cytokines. This result suggests the potential for these Abs to be used clinically without induction of a “cytokine storm”. To determine whether local depletion of T cells could be effected by genetically modified grafts, we generated Adv vectors expressing chimeric CD2hb11 or control Ig. Chimeric CD2hb11 secreted Ab from Adv-transduced pNICCs was able to bind human T cells. In Adv-transduced chimeric CD2hb11 pNICC grafted hu-SCID mice, a significant reduction (>60%) of human T lymphocytes was observed at the graft site leaving the peripheral immune system intact. We conclude that local production of a single antibody against T lymphocytes can reduce graft infiltration during xenotransplantation. Local production of immunosuppressive molecules limited to the graft site could afford protection from immune attack without affecting the immune system systemically thus educing fewer side effects.
Victorian State Government Operational Infrastructure Support. Australian Government NH&MRC IRIIS. Juvenile Diabetes Research Foundation. Australian National Health and Medical Research Council. Rebecca L. Cooper Foundation.
 Xenotransplantation (2013) doi:10.1111/xen.12025
11:00 - 12:30
|Islet Xenotransplantation||Anti-CD2 producing pig xenografts effect localized depletion of human T cells in a humanized mouse model||Room 109|
15:30 - 17:00
|Immunology||Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a humanized mouse model||Room 111-112|