LEWIS RAT PANCREAS, BUT NOT CARDIAC XENOGRAFTS, ARE RESISTANT TO ANTI-GAL ANTIBODY MEDIATED HYPERACUTE REJECTION 1

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Abstract
The objective of this study was to evaluate the role ofanti-Gal Abs and non-anti-Gal Abs in hyperacute rejection (HAR) of concordantpancreas xenografts compared with heart xenografts. In addition, we testedwhether rejection of Lewis rat pancreas grafts was T-cell dependent and couldbe prevented by anti-T-celltreatment. To determine the role of anti-Gal Abs in the induction ofHAR, Lewis rat pancreas and heart xenografts were transplanted intoα1,3Galactosyltransferase knockout (GT-Ko) mice treated with normal humanserum (NHS) or hyperimmune serum, or into presensitized GT-Ko mice. Toinvestigate whether rejection of pancreas xenograft was mediated by a T-celldependent response, Lewis rat pancreas grafts were transplanted intostreptozotocin (STZ)-induced diabetic GT-Ko mice treated with FK506, anti-CD4mAbs (GK1.5), and thymectomy. Antidonor-specific IgM and IgG and anti-Gal Abswere analyzed by flow cytometry. Rejected and long-term surviving pancreasxenografts were assessed by functional (blood glucose) and histopathologicalexamination. HAR of Lewis rat pancreas xenografts could not be inducedby NHS (0.4 ml), whereas NHS (0.2 ml) resulted in HAR of Lewis heartxenografts. Infusion of Lewis rat-specific hyperimmune serum (0.2 ml) resultedin HAR of Lewis rat pancreas xenografts. In addition, second Lewis ratpancreas grafts were hyperacutely rejected by presensitized GT-Ko mice.Immunohistochemical staining showed a low expression of Galα1,3Gal antigenin the endocrine tissue compared with that in the cardiac grafts. The levelsof anti-Gal Abs in pancreas xenograft transplantation did not increase inGT-Ko mice after pancreas xenograft transplantation that was significantlyincreased after heart transplantation. FK506 treatment induced long-termsurvival of Lewis pancreas xenografts (mean survival time (MST) >90 days).Anti-CD4 treatment delayed rejection of Lewis rat pancreas xenografts with MSTof 34.3 days, whereas anti-CD4, in combination with thymectomy,synergistically prolonged survival of pancreas xenograft (MST=70.4days). Pancreas xenograft is resistant to anti-Gal Abs-induced HARbut is susceptible to anti-donor specific Abs. Rejection of Lewis pancreasxenograft in STZ-induced, diabetic, GT-Ko mice is T-celldependent.