Mammalian immune response to xenogeneic extracellular matrix scaffolds

Porcine Small Intestinal Submucosa (SIS) is an acellular, naturally derived extracellular matrix (ECM) that has been used as a xenogeneic scaffold for constructive tissue remodeling in numerous animal models and in more than 100,000 human patients today. To date there has been no evidence for rejection of this xenogeneic scaffold. We have examined the acellular SIS scaffold for the presence of galactosyl-α (1,3) galactose (Gal epitope) and found the epitope to be distributed transmurally throughout the SIS material. Exposure of human plasma to SIS shows predominant binding of the IgG ₂ immunoglobulin and lack of complement activation. The local tissue response in mice implanted with porcine derived SIS shows a cytokine profile consistent with a restricted Th2 restricted immune response. Specifically, there is an increase in IL-4 expression, an absence of interferon gamma expression, and an SIS specific antibody response restricted to the IgG ₁ isotype. Efforts to induce Th1 associated anti-SIS responses using IL-12, STAT-6 knockout mice or deliberate immunization with SIS extracts emulsified in Freund's adjuvant, failed to elicit SIS scaffold rejection in vivo. We conclude that the typical mammalian immune response to SIS is predominantly Th2-like, consistent with constructive tissue remodeling rather than rejection.