Islet using gaxenotransplantationl-deficient neonatal porcine donors improves engraftment and function

P. Thompson¹, I.R. Badell¹, M. Lowe¹, J. Cano¹, B. Wiseman², J. Logan², F. Leopardi¹, M. Song¹, R. Ruhil¹, E. Strobert³, G. Rayat⁴, G. Korbutt⁴, R. Rajotte⁴, N. Iwakoshi¹, C. Larsen¹, A.D. Kirk^1
1 Emory Transplant Center, Atlanta, USA; ² Fios Therapeutics, Rochester, USA; ³ Yerkes National Primate Research Center, Atlanta, USA; ⁴ Alberta Diabetes Institute, Edmonton, Canada

Objective: Galactose-α1,3-galactose (Gal) is the major target of preformed xenoreactive antibodies in humans. Gal-deficient donors confer a profound survival advantage in pig-to-primate solid organ transplant models; however, their benefit in islet xenotransplantation has not been clearly demonstrated. We directly compare the immunogenicity, survival and function of neonatal porcine islets (NPIs) from wild-type (WT) or galactosyl transferase knockout (GTKO) donors in a nonhuman primate model.

Methods: Islets were isolated from pancreata of 1 – 4 day old WT or GTKO porcine neonates. Rhesus macaques were rendered diabetic with streptozocin, and received an intraportal infusion of ~50,000 IEQ/kg of either WT (n=5) or GTKO (n=5) NPIs. All recipients underwent immunosuppression with αCD154 and αLFA-1 mAbs, CTLA4-Ig, and mycophenolate mofetil. Recipient blood glucose, transaminase, and serum anti-gal and non-gal antibody levels were used to monitor response to transplant. Islets were also evaluated for relative susceptibility to complement- and antibody-mediated injury in vitro.

Results: WT NPIs were more susceptible to antibody and complement binding and destruction than their GTKO counterparts in vitro. GTKO islet recipients had superior rates of engraftment; 4 of 5 GTKO versus 1 of 5 WT recipients achieved insulin-independent normoglycemia. Rejection-free survivals were 249, 99, 91 and 50 days for GTKO islet recipients and 137 days for the WT recipient. Transplantation of WT islets resulted in significantly greater transaminitis.There was no significant difference in xenoantibody production between groups.

Conclusions: Our results confirm that Gal is important in xenoislet transplantation. GTKO NPI recipients have improved rates of normoglycemia, likely due to decreased susceptibility of xenografts to innate immunity mediated by complement and preformed xenoantibody. Therefore, the use of GTKO donors is an important step towards improved consistency and interpretability of results in future xenoislet studies. These results corroborate the importance of innate immunity in cellular as well as solid organ transplantation.