Long‐term survival of mouse corpus callosum grafts in neonatal rat recipients, and the effect of host sensitization

Abstract

Previous studies have suggested that the incidence of spontaneous rejection among immunogenetically mismatched neural transplants in neonatal recipients varies significantly depending on the cellular composition of the graft material. For example, neuron-rich grafts of embryonic mouse retina generally survive for extended periods without showing signs of rejection after implantation into neonatal rats, whereas cortical xenografts, which contain abundant glial and endothelial cells as well as neurons, typically undergo rejection 4-6 weeks after implantation. To determine whether the presence of donor glia is responsible for this high incidence of spontaneous rejection, we examined the fate of a non-neuronal graft material composed predominantly of xenogeneic glial cells (post-natal day 3, PD3, CD-1 mouse corpus callosum) implanted into the mesencephalon of PD1 Sprague-Dawley rats. The distribution and survival of donor astrocytes were assessed using a monoclonal antibody specific for a mouse astrocyte surface antigen, M2. Thirteen of 16 animals sacrificed within 2 months of implantation had detectable transplants. In these animals, M2-positive cells frequently migrated well away from body of the graft, clustering in large numbers in several characteristic regions of the host brain. Unlike cortical grafts of similar age, the vast majority (93%) of callosal transplants showed no histological signs of rejection or major histocompatibility complex antigen expression in and around the transplant-derived cells. As previously noted in the neonatal retinal transplant paradigm, however, well-integrated 1-month-old corpus callosum grafts could be induced to reject by appropriate sensitization of the host immune system, implying that the host was not immunologically tolerant to the foreign neural graft. With longer survival times in unsensitized hosts, a progressively smaller percentage of animals had detectable donor astrocytes (5 of 10 animals at 3 months postimplantation and 4 of 16 animals at 4 months); in those 9 animals with surviving grafts, only small numbers of M2-positive cells were seen within the graft bed and surrounding host brain. However, only 2 of the 26 "long-term" animals showed evidence of graft rejection. These results indicate that mouse astrocytes show characteristic patterns of migration into the host brain when implanted into neonatal rats; however, these xenogeneic cells have a limited duration of survival. The infrequency with which even subtle signs of spontaneous rejection were detected in animals that had received corpus callosum xenografts suggests that an immune-mediated process is unlikely to be responsible for the time-dependent elimination of the donor astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts

“…Transplant-produced myelin must also be stable. Transplant rejection studies have shown that grafts containing predominantly glial cells exhibit a low incidence of spontaneous rejection (Pollack et al, 1992), while grafts with contaminating endothelial cells and other vascular bed components were rejected in nearly all cases (Marion et al, 1990). Therefore, we suggest that suspensions of purified, glial progenitors may be the donor material of choice.…”

“…Traces of MBPt debris were observed around the needle track and along the ventricle linings, suggesting that myelin was previously present, but eventually lost. Others (Suard et al, 1989;Pollack et al, 1992) have also noted a limited duration of survival of xenogenic glial transplants, the basis of which is uncertain.…”

Interpreting MHC class I expression and class I/class II reciprocity in the CNS: Reconciling divergent findings

“…Where class I expression cannot be definitively localized to individual cells, the possibility is left open that neural cells themselves are not class I + . In some transplantation studies, it has been found that MHC upregulation by nonneural cells can account for the increased MHC expression (Armstrong and Lampson, in preparation;Pollack et al, 1992). Increased concentration of class I or b2-m in serum or CSF may contribute to the diffuse stain, as pointed out by Gogate et al (19911, and discussed above.…”

“…An overall blush of class I stain can be seen even in normal brain (Lampson, 1990;Lampson and Hickey, 1986;Schultzberg et al, 1989). Diffuse upregulation of class I expression has been described in pathological tissue, for example, following transplantation (reviewed in Pollack et al, 1992) or infection (Gogate et al, 1991;Maehlen et al, 1989a;Schultzberg et al, 1989).…”

Systemic Immune Deviation in the Brain That Does Not Depend on the Integrity of the Blood-Brain Barrier

“…he CNS has been shown to be an immune privileged site where transplanted allogeneic tissue can survive for a prolonged period of time (1)(2)(3)(4). The classical description of immune privilege in the CNS invoked "immunological ignorance" as an explanation for prolonged survival of grafted tissue vis-à-vis conventional nonprivileged sites (1).…”