Interaction of baboon anti-alpha-galactosyl antibody with pig tissues

As barriers to xenotransplantation are surmounted, such as suppression of h yperacute rejection allowing improved graft survival, it becomes important to define longer-term host-xenograft interactions. To this end we have prep ared in baboons high titer anti-alpha-Galactosyl (alpha Gal) and anti-porci ne aortic endothelial cell antibodies, similar to human natural xenoantibod ies and reactive with epitopes of thyroglobulin, laminin, and heparan sulfa te proteoglycans. When injected into pigs with a protocol similar to that u sed in the rat to show the nephritogenic potential of heterologous anti-lam inin and anti-heparan sulfate proteoglycan antibodies, baboon immunoglobuli ns bound first to renal vascular endothelium, and later to interstitial cel ls, especially fibroblasts and macrophages, and to antigens in basement mem branes and extracellular matrix, where they colocalized with laminin- and h eparan sulfate proteoglycan-antibodies, and with bound Griffonia simplicifo lia B4. A similar binding was observed in other organs. The pigs did not de velop an acute complement-dependent inflammation, but rather chronic lesion s of the basement membranes and the extracellular matrix. Incubation of ren al fibroblasts with baboon anti-alpha-Galactosyl antibodies resulted in inc reased synthesis of transforming growth factor-beta and collagen, suggestin g a possible basis for the fibrotic response. The results demonstrate that in this experimental model a consequence of alpha Gal antibody interaction with porcine tissues, is immunoreactivity with alpha Gal on matrix molecule s and interstitial cells, priming mechanisms leading to fibrosis resembling that in chronic allograft rejection. The possibility that similar lesions may develop in long-surviving pig xenografts is discussed.