Immunological and Inflammtory Responses against Intrastriatal Neural Grafts in the Rat

Sammanfattning: Intracerebral neural transplantation offers a new strategy to combat Parkinson’s and Huntington’s diseases. However, a host immune response against a histoincompatible neural graft in the brain may jeopardize transplant survival. We transplanted dissociated mesencephalic tissue prepared from Sprague-Dawley (SD) (syngeneic), Lewis (allogeneic) rats or mice (xenogeneic), into 6-hydroxydopamine (6-OHDA) lesioned or normal striatum of SD rats. We addressed the following issues: (i) the survival of syngeneic, allogeneic and xenogeneic neural grafts at different time-points after transplantation and the time-pattern of inflammatory and immunological reactions against them. (ii) if a first intrastriatal neural allograft leads to rejection of a second genetically identical allograft. (iii) if neural allografts can survive in the hosts which are immunized using orthotopic skin allografts before and after intracerebral surgery. (iv) the importance of graft immunogenicity for graft survival by supplementing allogeneic neuronal cell suspension with allogeneic spleen cells from the same Lewis donor rats. (v) the impact of severe local inflammation induced by an intrastriatal injection of quinolinic acid on the survival of neural allografts. (vi) the effects of methylprednisolone on the survival of intrastriatal concordant neural xenografts from mice. The results show: (1) Syngeneic and allogeneic neural grafts can survive transplantation to the striatum for prolonged periods. The inflammatory or immunological responses against such grafts are only weak and transient. In contrast, concordant xenogeneic neural grafts are in most cases rejected rapidly. (2) Neural allografts are not rejected by a host which has already received genetically identical allografts before. (3) Neural allografts are rejected if the host is immunized by an orthotopic skin allograft 6 weeks prior to, at the same time as, or 2 weeks after, neural transplantation surgery. However, neural allografts are not always promptly rejected if the orthotopic skin grafting is performed 6 weeks after the neural transplantation, although there is a massive inflammatory and immunological response against them. By 12 weeks after skin grafting, most of these allografts are rejected. (4) Addition of allogeneic spleen cells increases the immunogenicity of neural allografts and leads to rejection of mixed allografts following transplantation. (5) Severe inflammation in the striatum induced by quinolinic acid injection does not result in the rejection of neural allografts. (6) Rejection of concordant neural xenografts can be prevented by systemic administration of a daily high dose of methylprednisolone. In conclusion, the brain is an immunologically privileged site, but this privilege is not absolute. In our animal model, intrastriatal neural allografts can achieve long-term survival probably due to a very low immunogenicity and lack of antigen presenting cells in the grafted neural tissue. Even if neural allografts are implanted in a brain region that is affected by severe inflammation, they survive without clear signs of rejection. Nevertheless, rejection of neural allografts can be induced if the hosts are efficiently immunized with the same alloantigens before or soon after transplantation, rather than at later time-points. Methylprednisolone can be used as an alternative immunosuppressive drug to prevent rejection of concordant intracerebral neural xenografts.