Ž . Transplant Immunology 9 2001 1927 Evidence for polyreactive xenoreactive antibodies in the repertoire of human anti-swine antibodies: the ‘next’ humoral barrier to xenotransplantation? Jeffrey G. Gaca a , Winston Lee a , Olcay Aksoy a , Steven J. Braedehoeft b , Gonzalo V. Gonzalez-Stawinski a , William Parker a , R. Duane Davis a,  a Department of Surgery, Duke Uni  ersity Medical Center, Box 3864, Durham, NC 27710, USA b Department of Pathology, Duke Uni  ersity Medical Center, Durham, NC 27710, USA Received 2 July 2001; accepted 31 July 2001 Abstract The xenoreactive nature of anti-Gal 1  3Gal antibodies, and to a lesser extent, polyreactive antibodies, has been characterized by a number of investigators. With the advent of therapies that avoid hyperacute xenograft rejection due to anti-Gal 1  3Gal antibodies coupled with the possible development of Gal 1  3Gal deficient swine, the Gal 1  3Gal antigen may soon cease to be a barrier to xenotransplantation. With this in mind, the potential xenoreactive nature of polyreactive antibodies was investigated Ž . Ž . using several approaches. The levels of polyreactive antibodies from the serum of newborn n 2 and adult n 4 baboons undergoing pulmonary xenotransplantation were evaluated. Depletion of 95% and 94% of total serum IgM, without any decrease in albumin levels, was observed in the newborn baboons. This finding indicates that the IgM present at birth and germ line Ž . polyreactive IgM was adsorbed by the xenografts. The depletion of polyreactive antibodies 43  83% reduction of anti-DNP IgM from adult baboons was also observed following pulmonary xenotransplantation or immunoadsorption therapy plus pulmonary xenotransplantation. Additional experiments using human cord serum indicated that most human polyreactive IgM were adsorbed by pig lung homogenate and that the human polyreactive IgM bound approximately two-fold more to immobilized pig lung antigens than to immobilized human lung antigens. These findings indicate that germline polyreactive antibodies are, for the most part, xenoreactive. These data suggest that polyreactive antibodies, although autoreactive, may be more xenoreactive than autoreactive.  2001 Elsevier Science B.V. All rights reserved. Keywords: Xenotransplantation; Polyreactive antibodies; Xenoreactive antibodies 1. Introduction The critical shortage of organs for transplantation has generated interest in pigs as possible sources of  organs for xenotransplantation 1 . However, antibodies play a critical role in the rejection process that prevents  Corresponding author. Tel.: 1-919-681-4760; fax: 1-919-681- 4797. Ž . E-mail address: davis053@mc.duke.edu R.D. Davis .  the use of such organs 2 . Previous studies in swine to primate xenotransplantation have demonstrated that hyperacute rejection is initiated by IgM natural anti-  body 3 . These natural IgM antibodies recognize the disaccharide Gal  1  3Gal expressed on swine endothe- lium and these antibodies play a crucial role in  xenograft hyperacute rejection 4 . If hyperacute rejec- tion is averted, anti-Gal  1  3Gal IgG antibodies may  cause acute vascular rejection 5 . Current research focusing on genetic manipulation has raised the possibility of the development of swine 0966-327401$ - see front matter  2001 Elsevier Science B.V. All rights reserved. Ž . PII: S 0 9 6 6 - 3 2 7 4 01 00047-8