Purpose: Successful implementation of neonatal porcine islet (NPI) xenotransplantation requires an understanding of the xenospecific immune elements influencing engraftment. To elucidate these early xenospecific processes, we applied a unique in vivo dual transplant model comparing alloislets (AI) to either wild type (WT) or 1,3 galactosyltransferase knockout (GKO) xenoislets.

Methods: Equivalent NPI and AI masses were infused into randomly assigned contralateral hemilivers of rhesus recipients via the right and left portal veins. Six primates received AI and WT NPIs; 3 were studied at one hour and 3 at 24 hours post-infusion. Assessment consisted of extensive liver sectioning with immunohistochemical staining for protein and cellular immune components with digital quantification. Three additional animals were rendered diabetic, and then administered AIs and GKO NPIs utilizing anti-LFA-1, anti-CD154, and CTLA-4Ig based immunosuppression. Livers histology from these animals was studied 7 days post-infusion.

Results: Porcine specific stains confirmed separation of NPIs and AIs by liver lobe (p<0.05). Within 24 hours, there was significantly higher NK cell infiltration (p<0.01 at 1 hour and p=0.03 at 24 hours) and apoptosis (p=0.02) in WT NPIs over AIs. At 7 days post infusion, macrophage (p=0.02) and NK cell (p=.05) staining was significantly stronger in GKO NPIs compared to AIs, with a similar trend in IgM and CD3 (T cell) staining. These recipients had improved glucose homeostasis with stronger insulin staining in AIs than GKO NPIs (p=0.02). C4d complement staining was also stronger in AIs than GKO NPIs (p=0.06).

Conclusions: The separation of islet preparations within an individual recipient creates a highly controlled environment to objectively compare two different islet phenotypes and the immunologic factors that affect their early engraftment. We demonstrate higher early apoptosis and NK cell infiltration specific to WT NPIs when compared to AIs. After a week, glucose homeostasis was dominated by AI likely due to physiologic differences. Rigorous costimulation/adhesion blockade still permits innate cellular responses towards GKO NPIs significantly greater than AIs. These data suggest a need to target elements of innate cellular immunity in order to improve xenoislet engraftment.

CITATION INFORMATION: Samy K, Martin B, Song M, Collins B, Gall E, Cano J, Farris A, Leopardi F, Kirk A. Comparison of Early Engraftment Immunobiology of Xenoislets and Alloislets in a Dual Transplant Model. Am J Transplant. 2016;16 (suppl 3).

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