Swine Leukocyte Antigen-12 Behaves Like a Swine Leukocyte Antigen Classical Class I Protein and is a Potential Xenoantigen in Humans

Background: Using pigs as tissue donors may eliminate the shortage of replacement organs. As in allotransplantation, antidonor antibodies cause xenotransplant failure. Many antibodies target products of the major histocompatibility complex. Pigs contain a novel major histocompatibility complex gene, swine leukocyte antigen-12 (SLA-12), which has been proposed to behave as a classical class I SLA protein. Though predicted to bind B2m and short peptides, the functionality of the SLA-12 protein remains uncertain. In addition, its similarity to classical class I SLA molecules suggests that the SLA-12 could be a xenoantigen. Here we tested these predictions. Methods: Protein modeling was used to compare SLA-12 and classical class I proteins SLA-1, SLA-2, and SLA-3. cDNA encoding an isoform of SLA-12 was introduced into a cell line devoid of HLA proteins. B2m binding of SLA-12 at the surface of this cell line was evaluated. In addition, expression of SLA-12 molecules was examined in these cells after disrupting the genes encoding the transporters of antigenic peptides for class I proteins. Serum samples collected from transplant patients were also tested for the presence of SLA-12-specific IgG and IgM. Results: Predictive algorithms indicate SLA-12 and classical class I SLA proteins have very similar structures. We observed strong biochemical similarities as well in that SLA-12 binds to B2m and peptides to become a stable cell surface protein. Finally, we observed that SLA-12-expressing cells bind more serum IgG and IgM from some transplant patients, indicating that it can be a xenoantigen. Conclusions: SLA-12 has marked structural and biochemical similarities with classical class I SLA proteins and may be another target of human anti-pig antibodies. Similar approaches may be successful in mitigating the antigenic issues of SLA-12, SLA-1, SLA-2, and SLA-3.