Xenogeneic extracellular matrix grafts elicit a Th2-restricted immune response

Background. Porcine small intestinal submucosa (SIS) is an acellular, natur ally derived extracellular matrix (ECM) that has been used for tissue remod eling and repair in numerous xenotransplantations. Although a vigorous immu ne response to xenogeneic extracellular matrix biomaterials is expected, to date there has been evidence for only normal tissue regeneration without a ny accompanying rejection. The purpose of this study was to determine the r eason for a lack of rejection. Methods. Mice were implanted s.c. with xenogeneic tissue, syngeneic tissue, or SIS, and the graft site analyzed histologically for rejection or accept ance. Additionally, graft site cytokine levels were determined by reverse t ranscriptase polymerase chain reaction and SIS-specific serum antibody isot ype levels were determined by ELISA. Results. Xenogeneically implanted mice showed an acute inflammatory respons e followed by chronic inflammation and ultimately graft necrosis, consisten t with rejection. Syngeneically or SIS implanted mice, however, showed an a cute inflammatory response that diminished such that the graft ultimately b ecame indistinguishable from native tissue, observations that are consisten t with graft acceptance, Graft site cytokine analysis showed an increase in interleukin-4 and an absence of interferon-gamma, In addition, mice implan ted with SIS produced a SIS-specific antibody response that was restricted to the IgG1 isotype, Reimplantation of SIS into mice led to a secondary ant i-SIS antibody response that was still restricted to IgG1, Similar results were observed with porcine submucosa derived from urinary bladder. To deter mine if the observed immune responses were T cell dependent, T cell KO mice were implanted with SIS. These mice expressed neither interleukin-4 at the implant site nor anti-SIS-specific serum antibodies but they did accept th e SIS graft. Conclusions, Porcine extracellular matrix elicits an immune response that i s predominately Th2-like, consistent with a remodeling reaction rather than rejection.