Porcine neural xenografts in the immunocompetent rat: Immune response following grafting of expanded neural precursor cells

Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use o f xenogeneic tissue transplantation for conditions such as Parkinson's dise ase. The current study sought to provide insight into the cellular componen ts of donor cell suspensions that are important in stimulating the host rej ection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neura l stem cell mitogens, epidermal growth factor and fibroblast growth factor- 2, have been used to isolate and expand populations of primordial neural pr ecursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised. In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. Wh ile equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive p rojections were present at all time-points, and two large grafts remained e ven at 60 days. Some grafts appeared to elicit minimal host immune response s at the time-points they were examined, although most did appear to be und ergoing a rejection process since a co-ordinated response involving host cy totoxic T-lymphocytes, microglia/wmacrophages, immunoglobulin M and complem ent could be demonstrated to varying degrees. Subsequent experiments went on to demonstrate further that expanded precurs or populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursor s. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations. The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral g-rafting is reduced when neural stem cell mitogens are used to expand precursor cells. The imp lications of these findings in the development of novel xenogeneic cellular therapies for neuro degenerative conditions such as Parkinson's disease ar e discussed. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights r eserved.