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(American Journal of Pathology. 1999;155:1635-1649.)
© 1999 American Society for Investigative Pathology

Regular Articles

Interaction of Baboon Anti--Galactosyl Antibody with Pig Tissues

Shoichi Maruyama^*, Edward Cantu, III, Cesare DeMartino^¶, Catherine Y. Wang, Jonathan Chen, Futwan Al-Mohanna^||, Shaheen M. Nakeeb^||, Vivette D’Agati^§, Benvenuto Pernis, Uri Galili^**, Gabriel Godman^§, David M. Stern^* and Giuseppe Andres^§

From the Departments of Physiology,^*
Surgery,
Microbiology,
and Pathology,^§
College of Physicians and Surgeons of Columbia University, New York, New York; Laboratorio Elettromicroscopia,^¶
Ospedale S. Gallicano, Rome, Italy; the Department of Biological and Medical Research,^||
King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; and the Department of Microbiology and Immunology,^**
Allegheny University, Hahnemann School of Medicine, Philadelphia, Pennsylvania

As barriers to xenotransplantation are surmounted, such as suppression of hyperacute rejection allowing improved graft survival, it becomes important to define longer-term host-xenograft interactions. To this end we have prepared in baboons high titer anti--Galactosyl (Gal) and anti-porcine aortic endothelial cell antibodies, similar to human natural xenoantibodies and reactive with epitopes of thyroglobulin, laminin, and heparan sulfate proteoglycans. When injected into pigs with a protocol similar to that used in the rat to show the nephritogenic potential of heterologous anti-laminin and anti-heparan sulfate proteoglycan antibodies, baboon immunoglobulins bound first to renal vascular endothelium, and later to interstitial cells, especially fibroblasts and macrophages, and to antigens in basement membranes and extracellular matrix, where they colocalized with laminin- and heparan sulfate proteoglycan-antibodies, and with bound Griffonia simplicifolia B4. A similar binding was observed in other organs. The pigs did not develop an acute complement-dependent inflammation, but rather chronic lesions of the basement membranes and the extracellular matrix. Incubation of renal fibroblasts with baboon anti--Galactosyl antibodies resulted in increased synthesis of transforming growth factor-ß and collagen, suggesting a possible basis for the fibrotic response. The results demonstrate that in this experimental model a consequence of Gal antibody interaction with porcine tissues, is immunoreactivity with Gal on matrix molecules 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.