ALLOGRAFTS OF CNS TISSUE POSSESS A BLOOD-BRAIN-BARRIER .3. NEUROPATHOLOGICAL, METHODOLOGICAL, AND IMMUNOLOGICAL CONSIDERATIONS

Development of a blood-brain barrier (BBB) within mammalian CNS grafts , placed either intracerebrally or peripherally, has been controversia l. Published data from this laboratory have emphasized the presence or the absence of a BBB within solid mammalian tissue or cell suspension grafts is determined intrinsically by the graft and not by the surrou nding host parenchyma (e.g., brain, kidney, testis, etc.). Nevertheles s, correctly interpreting whether or not a BBB exists within brain gra fts is manifested by methodologies employed to answer the question and by ensuing neuropathological and immunological consequences of intrac erebral grafting. The present study addresses these issues and suggest s misinterpretation for the absence of a BBB in brain grafts can be at tributed to: (1) rupture of interendothelial tight junctional complexe s in vessels of CNS grafts fixed by perfusion of the host; (2) damage to host vessels and BBB during the intracerebral grafting procedure; ( 3) graft placement in proximity to inherently permeable vessels (e.g., CNS sites lying outside the BBB) supplying the subarachnoid space/pia l surface and circumventricular organs such as the median eminence, ar ea postrema, and choroid plexus; and (4) graft rejection associated wi th antigen presenting cells and the host immune response. The latter i s prevalent in xenogeneic grafts and exists in allogeneic grafts with donor-host mismatch in the major and/or minor histocompatibility compl ex. CNS grafts between non-immunosuppressed outbred donor and host rat s of the same strain (e.g., Sprague Dawley or Wistar rats) can be reje cted by the host; these grafts exhibit populations of immunohistochemi cally identifiable major histopatibility complex class I + and class I I + cells (microglia, macrophages, etc.) and CD4 + T-helper and CD8 T-cytotoxic lymphocytes. PC 12 cell suspension grafts placed within th e CNS of non-immunosuppressed Sprague Dawley rats are rejected similar ly. Donor cells from solid CNS grafts placed intracerebrally and stain ed immunohistochemically for donor major histocompatibility complex (M HC) class I expression are identified within the host spleen and lymph nodes; these donor MHC expressing cells may initiate the host immune response subsequent to the cells entering the general circulation thro ugh host cerebral vessels damaged during graft placement. Rapid healin g of damaged cerebral vessels is stimulated with exogenously applied b asic fibroblast growth factor, which may prove helpful in reducing the potential entry of donor cells to the host circulation. These results have implication clinically for the intracerebral grafting of human f etal CNS cell suspensions. (C) 1994 Wiley-Liss, Inc.