Mechanisms of allograft rejection in the rat brain.
Embryonic rat hippocampal primordia from class I and class II major histoincompatible donors were transplanted into the hippocampus of adult rat hosts. The allografts were rejected by a specific host immune response, which was identified by reference to events at a histocompatible hippocampal primordial graft (syngeneic to the host) of similar embryonic age placed simultaneously in the contralateral hippocampus of the same hosts. The present combined light immunohistochemical and electron microscopic study was undertaken to elucidate the mechanism of induction of the immune response by a graft of a tissue which does not constitutively express major histocompatibility antigens, to identify which cells are involved, and how they enter the brain and attack the graft, and to look for possible sources of variability in the outcome of such an attack. Our main findings are (1) that host and graft microglia play a prominent role from the earliest stages, and throughout the evolution of the histological changes, (2) that the later entry of host dendritic cells, lymphocytes, and lymphoblasts (with associated mitoses) into the perivascular cuffs of the graft vasculature ensures that the local immune response becomes self-propagating, (3) that the allografted neurons are killed by host cytotoxic lymphocytes only after a previous encirclement by host macrophage-derived microglial cells, and (4) that the observed variability (especially within different regions of a single allograft) is associated not with failure of immune induction, but with local failure of the graft tissues to express allotypic major histocompatibility antigens. Our observations confirm that once the host immune system has been primed, local factors leading to the induction of transplant major histocompatibility complex antigens make histoincompatible intracerebral transplants of embryonic into adult brain tissue vulnerable to vigorous and effective immune attack. The histological picture of the immune response observed in our intracerebral allografts resembles that described in intraventricular allografts of embryonic brain, in allografts of other organs and tissues such as skin, kidney, and heart, and also that seen in the response to brain autoantigens in multiple sclerosis and experimental allergic encephalomyelitis. However, the involvement of a special cell type, the perivascular microglial cell, in the early stages of immune induction in brain raises the possibility of designing future therapeutic approaches which might selectively block this step in conditions such as multiple sclerosis.