Enhanced Survival of Porcine Neural Xenografts in Mice Lacking CD1d1, But No Effect of NK1.1 Depletion

Abstract

Transplantation of embryonic porcine neurons may restore neurological function in patients with Parkinson's disease, if immunological rejection could be prevented. This study was performed to investigate the role of natural killer cells (NK cells) and NK1.1+ T cells (NK T cells) in the rejection of neural xenografts. A cell suspension was prepared from the ventral mesencephalon of 26-27-day-old pig embryos, and 2 microl was implanted in the right striata of mutant CD1d1 null (CD1.1-/-) mice, NK1.1-depleted mice, and controls. The CD1.1-/- mice are deficient in NK T cells and the antigen-presenting molecule CD1d1. Graft survival and host responses were determined immunohistochemically using markers for dopamine neurons, CD4-, CD8- cells, microglia, and macrophages. At 2 weeks, the grafts were significantly larger in CD1.1-/- mice, 0.09 +/- 0.02 microl (mean +/- SEM), compared with controls, 0.05 +/- 0.01 microl. There was no significant difference between NK1.1-depleted mice, 0.02 +/- 0.01 microl, and controls. At 5 weeks, two grafts were still present in the CD1-/- mice, whereas only scars remained in the controls and in the NK1.1-depleted mice. Immune reactions were strong at 2 weeks and less pronounced at 5 weeks in all groups. Microglial activation was lower in NK-depleted mice than in the controls at 2 weeks. In contrast to organ xenografting, NK1.1+ cells do not seem to be important mediators of the rejection of discordant cellular neural xenografts. However, our results suggest that the antigen-presenting molecule CD1d1 may be involved in the rejection process.

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

“…Scars were found in all control mice except one, where a very small graft was present, and none of the control mice had any TH-positive neurons. This is consistent with our previous studies where porcine neural xenografts in untreated wild-type mice have invariably been rejected within 2 wk [17,18]. In the untreated CD40L-/-mice and the CD40L-/-mice that received mono-therapy of either anti-LFA-1 or CTLA4Ig, graft condition was more variable.…”

“…Several studies have been performed in order to characterize the immune response against discordant neural xenografts, as reviewed in Brevig et al [16]. It has been shown that xenograft rejection was delayed up to 4 wk in both immunoglobulin-and CD1.1-deficient mice, but eventually occurred in all animals [17,18]. In contrast to organ xenografting, NK cells do not seem to be important for the rejection process against a cellular graft in the brain [18].…”

Natural Killer T-Cells Participate in Rejection of Islet Allografts in the Liver of Mice

“…In contrast to these findings, human CD1d (hCD1d) has been reported to function as a transplantation antigen, and skin grafts are rejected by expression of human CD1d in the major histocompatibility complex-matched mouse model (38). Survival of porcine neural xenografts is shown to be enhanced in the brain of CD1d Ϫ/Ϫ mice compared with wild-type controls (39). Recently, Oh et al (40) reported that rejection of H-Y mismatched skin grafts is accelerated in CD1d Ϫ/Ϫ mice as recipients compared with wild-type mice.…”

Activated Porcine Embryonic Brain Endothelial Cells Induce a Proliferative Human T-Lymphocyte Response

“…The (PBMEC) might be highly immunogenic in the pig-tohuman situation, where the relationship between direct involvement of immunoglobulins (31,54), complement (1) (Larsson, Sumitran-Holgersson, Korsgren, Holgersand indirect antigen recognition is more balanced. In the present study, our aim was to determine whether son, and Widner, manuscript in preparation), natural killer (NK) cells (53), and NK T cells (29) in neural xeno-PBMEC could induce a human T-cell response via the direct pathway of antigen recognition. Resting PBMEC, graft rejection have also been suggested, as reviewed in Brevig et al (4).…”