Absence of humoral and cellular alloreactivity in baboons sensitized to pig antigens

Abstract

to study whether sensitization to pig antigens results in humoral and/or cellular sensitization to alloantigens in baboons, and thus increases the risks of organ allotransplantation after xenotransplantation. Serum from baboons that were naive (n = 4), sensitized to Gal alpha 1,3Gal (Gal) antigens (n = 2), or sensitized to Gal + non-Gal pig antigens (n = 2) were tested by flow cytometry for the presence of immunoglobulin G (IgG) and IgM antibodies that bind to pig or baboon peripheral blood mononuclear cells (PBMC). Two allosensitized baboons were used as positive controls. The same 10 sera were tested in a complement-mediated cytotoxicity assay to detect cytotoxic antibodies against pig, allo and self-PBMC. The T-cell responses of the same baboons to allogeneic and pig PBMC stimulators in mixed lymphocyte reaction (MLR) were studied. All baboon sera contained cytotoxic antibodies that bound to pig PBMC. Binding and cytotoxicity were higher in xenosensitized baboons, particularly in those sensitized to Gal + non-Gal antigens (P < 0.001). None of the naive or xenosensitized baboon sera bound to baboon PBMC. Serum from allosensitized baboons showed anti-baboon IgG and IgM binding, but there was no increase in binding to pig PBMC or in cytotoxicity to pig cells. The MLR response to pig stimulators in baboons sensitized to non-Gal pig antigens was greater than that of naive or Gal-sensitized baboons (P < 0.001), but there was no increase in the response to baboon cells. In baboons, no in vitro evidence that a previous pig xenograft might endanger the outcome of a subsequent allograft was documented.

Antibody Mediated Rejection in Pig-To-Nonhuman Primate Xenotransplantation Models

“…In addition, baboons sensitized to pig antigens did not appear to have a higher sensitization profile towards allogeneic products compared to naïve animals [116]. Taken together, the available information on the relationship between HLA and SLA is not sufficient to enable firm conclusions to be drawn at this stage and further investigations are eagerly awaited to shed some light on the subject.…”

Using α1,3-galactosyltransferase gene-knockout pig organs in nonhuman primates

“…It was demonstrated that allosensitization does not increase the risk of antibody-mediated rejection of a GT-KO pig organ, as the extent of human antibody binding and cytotoxicity to GT-KO PBMC did not differ from unsensitized humans [23 ,50 ]. Furthermore, previous studies have indicated that baboons sensitized to pig antigens did not develop antibodies that cross-reacted with baboon alloantigens, offering the opportunity of using a pig organ to act as a 'bridge' until a human organ becomes available [51]. Before xenotransplanatation can proceed to the clinic, however, further life-supporting pig-to-NHP organ transplantation experiments, with a clinically relevant and well tolerated immunosuppressive regimen, will have to show extended graft and recipient survival.…”

Pig–to–Non-human Primate Heart Transplantation: Immunologic Progress Over 20 Years

“…71 Later in vitro studies confirmed that, despite the development of high levels of elicited anti-pig Abs, baboons did not develop allosensitization. 72 This would enable a pig organ to be used successfully as a bridge to allotransplantation. 5.…”