Neonatal porcine islet cells induce human CD4(+), but not CD8(+), lymphocyte proliferation and resist cell-mediated cytolytic injury in vitro

Xenotransplantation of porcine tissue to human recipients promises to allev iate the organ shortage. Human antibody-mediated and cell-mediated immune r esponses against porcine grafts, however, represent barriers to successful xenotransplantation. We compared neonatal porcine islet cells (NPICs) and n eonatal porcine splenocytes for the ability to stimulate proliferation of h uman peripheral blood lymphocytes (PBLs), and for their susceptibility to h uman natural killer (NK) and cytotoxic T-lymphocyte (CTL)-mediated lysis, H uman peripheral blood CD4(+) lymphocytes showed strong proliferation in res ponse to NPICs, likely because of occasional swine leukocyte antigen (SLA) class II+ cells in the NPIC preparations. In contrast, human peripheral blo od CD8(+) lymphocytes did not proliferate in response to NPICs, although th ey showed clear responses to both porcine splenocytes and endothelial cells , Both human CTL-raised-against-porcine splenocytes and endogenous NK cells lysed porcine splenocytes,but the same cells showed little or no lytic act ivity against NPICs, Lysis of porcine splenocyte targets was completely abr ogated by pretreatment of the human NK or CTL populations with concana-myci n A, suggesting a perforin-dependent effector mechanism. Pretreatment of th e NPIC targets with proinflammatory porcine cytokines to upregulate SLA cla ss I expression failed to enhance human CTL-mediated lysis. However, lysis of NPICs by human CTLs could be elicited when a lectin was added to form st able effector:target cell conjugates. It appears that NPICs do not express sufficiently high levels of co-stimulatory and/or adhesion molecules to eit her activate human CD8+ T-cells or to be effective targets for activated hu man CTLs, These data suggest that NPICs may not be destroyed by NK- or CTL- mediated lytic mechanisms after transplantation into humans.