Instability of Neural Xenografts Placed in Neonatal Rat Brains

Rd, Lund; K, Rao; Hw, Kunz; Tj, Gill

doi:10.1097/00007890-198808000-00006

Cited by 45 publications

(15 citation statements)

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“…These histological findings indicate that the rat PC12 cells were eventually rejected by the mouse host brain after an initial phase of proliferation. Such interpretation of their disappearance is consistent with previous observations that cross-species brain transplants initiate host vs. graft responses (18,19).…”

Section: Transplantation Of Transfected Pc12 Cells Into Brains Ofsupporting

confidence: 91%

Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo.

Neve

Kammesheidt

Höhmann

1992

Proc. Natl. Acad. Sci. U.S.A.

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PC12 cells transfected with retroviral recombinants expressing the carboxyl-terminal 104 amino acids ofthe Alzheimer amyloid protein precursor (QAPP-C104) or PC12 cells transfected with the retroviral vector (DO) alone were transplanted into the brains of newborn mice. At 20 days after grafting, transplants could be detected in -all of the mouse brains examined. At 4 months after transplantation, experimental animals exhibited significant cortical atrophy. Some also revealed immunoreactivity with Alz-50, an antibody that detects an Alzheimer disease-related protein, in the somatodendritic domain of neurons in the cortex surrounding the transplants. In addition, disorganization of the neuropil in the CA2/3 region of the hippocampus ipsilateral to the transplant was revealed by staining with an antibody to the carboxylterminal end of the amyloid protein precursor. A decrease in cell body immunoreactivity for this portion of the amyloid protein precursor was also detected with this antibody. Together, these results suggest that the carboxyl-terminal fragment of I3APP may cause specific neuropathology and neurodegeneration in vivo.One of the hallmarks of Alzheimer disease pathology is the deposition of amyloid in neuritic plaques and along the walls of the cerebral vasculature (1-4). The principal component of amyloid is a 4-kDa protein termed 83/A4 (5-7). Recent evidence indicates that normal processing of the amyloid protein precursor (,8APP) is a membrane-associated event that occurs within the extracellular domain of f3/A4 (8,9). Hence, the generation of 8/A4 in Alzheimer disease appears to be the result of abnormal cleavage. However, the molecular mechanisms of amyloidogenesis, as well as the role of amyloidogenesis in the development of Alzheimer disease pathology, remain unclear.Recent evidence has implicated a carboxyl-terminal fragment of f3APP in the processes of amyloidogenesis and neurodegeneration. This fragment, which spans the f3/A4 and cytoplasmic domains, has a tendency to self-aggregate (10). Moreover, expression of this carboxyl-terminal 3APP fragment in primate cells has been shown to lead to the production of a 16-kDa protein that aggregates and accumulates into deposit-like structures (11) and to result in the formation of amyloid-like fibrils (12).We have shown that this same carboxyl-terminal I3APP fragment is neurotoxic (13). PC12 cells transfected with a retroviral recombinant expressing the carboxyl-terminal 104 amino acids of SAPP (formerly termed AB1, ref. 13; now termed /3APP-C104) degenerate when induced to differentiate into neuronal cells with nerve growth factor (13). To test the hypothesis that this neurotoxic carboxyl-terminal f3APP fragment may play a role not only in amyloidogenesis but also in the development of the progressive neuropathology of Alzheimer disease, we transplanted cells expressing this fragment into the brains of newborn mice. We report here that animals transplanted with 8APP-104-transfected PC12 cells exhibited gross cortical atrophy by 4 months after ...

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Section: Transplantation Of Transfected Pc12 Cells Into Brains Ofsupporting

confidence: 91%

Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo.

Neve

Kammesheidt

Höhmann

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the 3 animals without transplants all had detectable injection tracks characterized by a thin line of enhanced astrocytic and microglial staining extending inward from the surface of the brainstem, there was no evidence of lymphocytic infiltration or MHC immunoreactivity to suggest that these grafts had been destroyed by immunological attack. In previous studies involving retinal allografts and xenografts to neonates, a similar proportion of animals without grafts has been found (Lund et al, 1987(Lund et al, , 1988; this can be attributed to inadvertent extrusion of the graft from the injection site because of the loose structure of the surrounding immature brain.…”

Section: Graft Survival and Astrocyte Migrationsupporting

confidence: 54%

“…In either case, the stimulus for graft rejection is highly sitespecific. As noted previously with retinal xenografts (Lund et al, 1988;, whereas virtually all callosal transplants are induced to reject after skin grafting, only grafts located in the vicinity of degenerating optic axons undergo rejection after eye removal; more ventrally located tegmental grafts remain unaffected. The character of the rejection response after skin grafting also shows substantial differences from that following eye removal.…”

Section: Role Of Graft Composition In Determining Transplant Survivalsupporting

confidence: 54%

“…Therefore, the bloodbrain barrier (BBB) disruption Broadwell et al, 1990) and inflammatory reaction, which are inevitable consequences of the transplantation procedure, may resolve before the host is capable of initiating rejection. This is significant because stably integrated grafts placed in neonates consistently undergo rejection following the induction of neural degeneration (Lund et al, 1988; or BBB disruption in the region of the graft after the animals have reached adulthood. The neonatal paradigm therefore facilitates a detailed analysis of the factors that contribute to graft rejection apart from those relating to the trauma associated with the implantation procedure itself.…”

Section: Introductionmentioning

confidence: 99%

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

Pollack

Lee

Zhou

et al. 1992

J of Neuroscience Research

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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)

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“…It is now clear that the CNS is not the "immunologically privileged" region that it was thought to be (Borgeson et al, 1989;Lund et al, 1989;Streilein, 1988). The CNS is capable of rejecting allogeneic neural tissues grafted into the CNS (Date et al, 1988;Kerr and Bartlett, 1989;Lund et al, 1988Lund et al, , 1989Nicholas et al, 1987;Rao et al, 1989). A require-ment for immunological rejection is that the transplanted cell express appropriate foreign and MHC antigens (Streilein, 1988;Zinkernagel and Doherty, 1974).…”

Section: Discussionmentioning

confidence: 99%

Transplantation of a temperature‐sensitive, nerve growth factor‐secreting, neuroblastoma cell line into adult rats with fimbria–fornix lesions rescues cholinergic septal neurons

Whittemore

Holets

Keane

et al. 1991

J of Neuroscience Research

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The HT4 cell line was derived from infection of a mouse neuroblastoma cell line with a retrovirus that encoded the temperature-sensitive (ts) mutant of SV40 large T antigen. At nonpermissive temperature, HT4 cells differentiated with neuronal morphology, expressed neuronal antigens, synthesized nerve growth factor (NGF) mRNA, and secreted biologically active NGF in vitro. We sought to establish whether transplanted HT4 cells expressed class I major histocompatibility complex (MHC) antigens, a partial requirement for recognition by cytotoxic T lymphocytes (CTL), and thus be susceptible to xenograft rejection. Differentiated HT4 cells expressed marginally detectable levels of class I MHC antigens, but demonstrated higher levels of class I MHC expression after treatment with interferon-gamma. However, HT4 cells were resistant to direct lysis by perforin, the pore-forming protein of CTLs, and thus may have potential use in xenograft experiments. To address whether HT4 cells secrete NGF in vivo, HT4 cells were transplanted into adults rats with unilateral fimbria-fornix transections. A ts cell line derived from P4 cerebellum, BT1, that does not differentiate with neuronal phenotype or synthesize NGF in vitro, was transplanted as a control. Six weeks posttransplant. HT4 cells had integrated into host CNS without forming tumors. In BT1 transplants, the number of medial septal acetylcholinesterase (AChE)-positive cells was reduced to 26-39% of the contralateral control side, depending on the rostrocaudal level. In HT4 transplants, the number of cholinergic septal neurons was 58-78% of the contralateral side. This percentage was significantly (P less than 0.005) greater than that seen with BT1 transplants, indicating that transplanted HT4 cells secrete NGF in vivo and rescue cholinergic septal neurons following fimbria-fornix transection.

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Instability of Neural Xenografts Placed in Neonatal Rat Brains

Cited by 45 publications

References 0 publications

Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo.

Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo.

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

Transplantation of a temperature‐sensitive, nerve growth factor‐secreting, neuroblastoma cell line into adult rats with fimbria–fornix lesions rescues cholinergic septal neurons

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