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R D Lund

Publications and source records attributed to R D Lund.

At least 91 records · Page 5Linked to original sources
PubMed1990

Proximity as a factor in the innervation of host brain regions by retinal transplants.

Embryonic mouse retinae transplanted to a variety of locations within the rostral midbrain of neonatal rats exhibit selective innervation of host visual nuclei when studied at maturity. Some of these nuclei (superior colliculus, nucleus of the optic tract, dorsal terminal nucleus) usually receive extensive transplant projections, others are innervated partially (dorsal division of the lateral geniculate nucleus, olivary pretectal nucleus, medial terminal nucleus), while a few (ventral division of the lateral geniculate nucleus, suprachiasmatic nucleus, intergeniculate leaflet) are not innervated at all. The selectivity of this innervation is largely independent of the transplant's position within the rostral brainstem, while the density of innervation of individual nuclei depends in part upon the proximity of the transplant to the nucleus and upon whether the host retinal projection to that nucleus is present or absent. These findings provide a foundation for further studies of the behavioral capabilities of retinal transplants, for developmental studies of factors responsible for the establishment of normal neural projections, and for examination of the immunological consequences of transplantation.

Animals↗
PubMed1990

Patterns of immune rejection of mouse neocortex transplanted into neonatal rat brain, and effects of host immunosuppression.

We studied the histological and immunological characteristics of graft rejection in the rodent central nervous system (CNS) using embryonic mouse neocortex transplanted into the CNS of neonatal rats. Grafts from animals aged 8-145 days (n = 210) were examined using standard histological techniques for demonstrating cell morphology and fiber projections. Immunohistochemical techniques were used to identify graft projections into the host CNS. The incidence of graft rejection was 18% for animals between 18 and 30 days of age, but increased abruptly to 73% for animals older than 30 days. No graft rejection was seen in animals younger than 18 days. In a smaller group of xenograft recipient rats sacrificed at specific time points before and after one month of age, detailed immunohistochemical studies were performed to correlate the histological appearance of the graft with the level of major histocompatibility complex (MHC) class I and II immunoreactivity, and microglial, astrocytic and lymphocytic staining within the graft and host brain. Evidence of mild rejection as manifested by the appearance of scattered lymphocytes within the graft coincided with the development of Class I and II immunoreactivity within the graft and at the graft-host interface, which was demonstrated in some animals as early as 24 days. At 29 days of age, rejecting grafts showed diffuse MHC expression within the graft and at the graft-host interface; in contrast, unrejected grafts failed to show MHC immunoreactivity. Thirty-four day-old grafts often showed severe rejection with perivascular lymphocytic cuffing within the graft and in host parenchyma remote from the graft associated with increased MHC immunoreactivity within the host brain. In grafts older than 34 days there was frequently a violent rejection reaction with disruption of the cytoarchitecture of the graft and surrounding host tissues, and widespread MHC antigen expression. Immunosuppression with cyclosporin A was effective in avoiding rejection. The high incidence of rejection with neocortical xenografts is in striking contrast to the much lower incidence seen with retinal xenografts. This suggests that there are immunological features unique to neocortex which incite host recognition and rejection.

Animals↗
PubMed1990

Cellular events associated with peripherally induced rejection of mature neural xenografts placed into neonatal rat brains.

Various circumstances have brought about a dispute concerning the immunologically priviledged status of the central nervous system (CNS). Using a transplantation paradigm, we have examined the cellular events associated with an experimentally induced focal assault on the CNS by the immune system. Chunks of embryonic mouse cortex were transplanted into neonatal rat brains and allowed to survive for 4 weeks. The adult rats then received a skin graft of donor origin to induce rejection of the transplanted tissue. Animals were sacrificed at various time points and examined histologically and immunocytochemically. Under these circumstances, the transplant is rejected via a first-set rejection response, and astrocytes of donor origin appear to be the primary target of the host immune system. Expression of class I and class II major histocompatibility antigens is noted to correlate with lymphocytic invasion of the transplant.

Animals↗
PubMed1990

Amphetamine sensitization of stress-induced turning in animals given unilateral dopamine transplants in infancy.

Infant rats given bilateral dopamine-depleting brain lesions and unilateral transplants of embryonic nigral tissue develop turning in response to both amphetamine and stress. However, stress-induced turning did not develop unless animals were previously exposed to amphetamine, and was greatest in animals exposed early to the drug. These findings suggest that amphetamine alters certain properties of the transplanted cells so as to enhance their functional capacity.

Amphetamines↗
PubMed1990

Timing and patterns of astrocyte migration from xenogeneic transplants of the cortex and corpus callosum.

The timing, pattern, and pathway of astrocyte migration were investigated in vivo by transplantation of CD-1 mouse cerebral cortex (E13-14) or corpus callosum (P2-3) into neonatal rat cortex. A monoclonal antibody specific for a mouse astrocyte surface antigen (M2) was used to identify the location of the grafts and the migrated donor astrocytes. Within the host cortex, astrocytes from cortical grafts began migration at post-transplantation day (PTD) 7. Over the next 4 days, the most distant displaced donor cells were found progressively further away from the grafts, migrating at a rate of about 220 microns/day. After PTD 11, the migration rate for the farthest displaced donor cells slowed to 25 microns/day, and the cells appeared to stop at about PTD 16 at a distance of 1,100 microns from the edge of the graft. Astrocytes had a faster migration speed in the white matter and covered a longer distance (5 mm) than those in the gray matter, extending on occasion into the contralateral hemisphere. The patterns of astrocyte migration differed depending on local cues around the transplant. Donor astrocytes that had been implanted into the host cortex migrated toward the host cortical surface, sometimes in several radial lines. Astrocytes from grafts, especially callosal grafts, placed in the subcortical white matter migrated along the host fiber tracts. Many astrocytes transplanted into the hippocampus formed laminar patterns close to the hippocampal neuronal layers. These results suggest that the direction, pattern, and speed of astrocyte migration are influenced by local substrates in the host brain.

Animals↗
PubMed1990

Directed early axonal outgrowth from retinal transplants into host rat brains.

Axons from retinae transplanted to the brain stem of neonatal rats exhibit two patterns of outgrowth that can be experimentally uncoupled from each other depending upon the location of the graft. Retinae placed close to the surface of the rostral brain stem (as much as 5 mm from the tectum) emit axons that project toward the superior colliculus along the subpial margin of the rostral brain stem. In contrast, axons from grafts embedded deep within the midbrain parenchyma project through the neuropil directly to the overlying superior colliculus, as long as the retina is within about 1 mm of the tectal surface. The present study shows that, as long as the retina is located outside the superior colliculus, and regardless of whether the axons derive from grafts in subpial or intraparenchymal locations, the earliest projections are oriented towards the superior colliculus. We have also found, however, that axons from retinae transplanted directly onto the superior colliculus can form projections that extend along the subpial margin away from the tectum. There are several major conclusions that may be drawn from these observations. First, the final tectopetal, transplant-derived projection does not result from the reorganization of an initially random outgrowth but is directed from the start toward an appropriate region of termination. Second, it appears that the interaction of retinal axons with a primary target alters the ability of the growth cone to respond to directional cues along the optic tract. Thus, although adding support to the proposal that optic axons attain the superior colliculus through an interaction involving substrates distributed along the optic tract and diffusible factors originating in the target region, it is increasingly clear that such interactions are likely to be complex and hierarchical.

Animals↗
PubMed1990

Evidence that the lamina cribrosa prevents intraretinal myelination of retinal ganglion cell axons.

In the majority of mammals axons of retinal ganglion cells are not normally myelinated intraretinally. To test the hypothesis that the lamina cribrosa normally prevents myelin-forming cells from entering the retina we have examined the axons of retinal ganglion cells in conditions where there is no lamina cribrosa. Following transplantation of fetal retinae to the midbrain of newborn rats we have shown that ganglion cell axons within the transplants subsequently become myelinated, providing further evidence that the intraretinal segment of a ganglion cell axon is not refractory to myelination if myelin-forming cells are allowed access. Thus, our results support the hypothesis that the lamina cribrosa normally prevents oligodendrocytes or their precursors from gaining access to the retina. A number of factors may be involved in restricting the migration and differentiation of myelin-forming cells but it is apparent that there is a correlation between the absence or paucity of myelination and the presence of locally increased permeability of the blood-brain barrier. We suggest that proteins derived from plasma may influence oligodendrocyte precursor migration and/or differentiation at these sites.

Animals↗
PubMed1990

Induction of target-directed optic axon outgrowth: effect of retinae transplanted to anophthalmic mice.

In previous work using neural transplants (Hankin and Lund, 1987) we demonstrated two basic components of optic axon outgrowth in the mammalian retinotectal system: one category of outgrowth utilizes the subpial margin of the rostral brain stem as a preferential substrate (as do normal retinotectal axons); the other type of outgrowth, from retinae embedded deep within the midbrain parenchyma, is distance-dependent and highly target-oriented, but shows little apparent substrate specificity. One explanation for this directed outgrowth is that it is in response to a diffusible factor emanating from cells in the superior colliculus. In the present study we use congenitally anophthalmic mice as recipients for retinal transplants to test whether prior optic innervation of the superior colliculus plays a role in establishing either component of outgrowth. We show that outgrowth along the subpial pathway from a graft placed on the surface of the brain stem can take place in the absence of prior innervation of the superior colliculus. The target-directed outgrowth exhibited by embedded grafts only occurs if the tectum is also innervated by a second graft placed on the surface of the brain stem. It is proposed that tectal cells produce a factor in response to optic innervation and that this directs the growth patterns of embedded grafts. This suggests that optic innervation is a necessary prerequisite for the superior colliculus to produce the proposed diffusible chemotropic signal. In normal development such a factor could function to improve the efficiency of target-finding by later growing optic axons, but it might serve a quite different role, encouraging branching and trophic maintenance of the optic pathway once it has reached the tectum.

Animals↗
PubMed1990

The blood-brain barrier protects foreign antigens in the brain from immune attack.

To examine the role of the blood-brain barrier (BBB) in maintaining immune privilege in the brain, the BBB in the region of stably integrated mouse neural grafts implanted in neonatal rat brains was transiently disrupted by intracarotid infusion of hypertonic mannitol. This led to graft rejection and to prominent expression of major histocompatibility complex (MHC) antigens on cells adjacent to the graft. Grafts in control animals receiving an intracarotid infusion of isotonic saline showed only rare MHC expression and no increased incidence of rejection. Opening the barrier in the absence of a graft caused neither MHC expression nor cellular infiltration within the brain, suggesting that the effects of the hypertonic infusion were not produced by an indirect injury-mediated effect on the host brain. We conclude that the integrity of the blood-brain barrier is an important factor in the relative immune privilege of nonsyngeneic neural grafts.

Animals↗
PubMed1990

Retinal graft-mediated pupillary responses in rats: restoration of a reflex function in the mature mammalian brain.

We have shown previously that fetal retinae transplanted to neonatal rat brains are capable of making the pretectal connections necessary for driving a pupillary reflex in response to light. At birth, the rat brain is still developing and presents a favorable environment for fiber outgrowth and synaptogenesis. A remaining question is whether such grafts will also establish functional connections within the less plastic mature brain. Fetal retinae taken from Sprague-Dawley rats at embryonic day 13 or 14 were implanted in the pretectal region of mature host rats ranging in age from 6 to 11 weeks. The contralateral host eye was removed to reduce afferent competition within the pretectum between the optic input of graft and host. The remaining host optic nerve was cut before testing to eliminate all remaining host visual input. Beginning 1 month after transplantation, the retinae were surgically exposed and illuminated. In 6 of 24 animals, illumination elicited an obvious pupilloconstriction response in the host eye. The magnitude of this graft-mediated response varied between animals. Two animals produced very brisk responses, comparable to the best results seen following transplantation into neonatal hosts. In these cases, the degree of constriction was clearly dependent on the level of graft illumination. The 4 other animals produced responses that were less brisk. All 6 animals with clear-cut graft-mediated pupillary responses had well-formed grafts containing numerous rosettes and ganglion cells. In addition to these 6 animals, 9 others showed extremely small or variable pupillary changes on graft illumination. The remaining 9 animals showed no stimulus-associated pupillary activity. Grafts in this group tended to be poorly formed or were located outside the pretectal area. These results show that transplanted retinae are capable of making specific functional connections with the mature brain, since an appropriate visual reflex can be elicited by illuminating the graft in the absence of host visual input.

Aging↗
PubMed1989

Degeneration of optic axons induces the expression of major histocompatibility antigens.

Eye removal from adult rats causes induction of major histocompatibility complex (MHC) antigen expression by cells within areas of optic terminal degeneration. Class I MHC antigen expression occurs through the degenerating optic terminal areas, while class II MHC antigen expression is found within areas of degenerating myelinated axons. This could be an important step in the process of immunological recognition and subsequent rejection of neural transplants that are located in the region of the degenerating fibers. It could also be a precipitating factor in certain neurodegenerative diseases of the central nervous system.

Animals↗
PubMed1989

Implantation of tissue into the brain. An immunologic perspective.

The transplantation of neural tissue into the brain has the potential to repair the effects of trauma and of congenital abnormalities and to replace tissue that has ceased to function as the result of disease. The brain is not an immunologically privileged site in the strict sense; under certain carefully defined circumstances, grafts can last for long periods of time, but many such grafts are rejected naturally or following various types of provocation. Factors important to the survival of neural grafts are the use of embryonic tissue, the immunogenetic match, the level of expression of major histocompatibility complex antigens in brain cells close to the graft, and the presence of neural degeneration near the graft. Much additional basic experimental work must be done, however, before a rational approach to the clinical use of neural grafts can be undertaken.

Adult↗
PubMed1989

Integrity of the blood-brain barrier in retinal xenografts is correlated with the immunological status of the host.

The purpose of this study was to determine the immunological correlates of blood-brain barrier breakdown in retinal xenografts in rats by utilizing skin grafting to initiate a timed immune response to the transplanted neural tissue. Embryonic day 13-14 CD-1 mouse retinae were grafted into the brainstem parenchyma of neonatal Sprague-Dawley rats. In one group of animals a 100 mm2 CD-1 skin graft was placed on the flank 21 days after the initial neural transplant in order to provoke an immune response to the neural graft. Control animals received no skin graft. Animals were injected with horseradish peroxidase (HRP) in the femoral vein 2-8 days after skin grafting. Brains were processed for Nissl, HRP-tetramethylbenzidine, and anti-M-6, -lymphocyte, -macrophage, and -astrocyte antibodies. Experimental and control animals injected 2-4 days after skin grafting showed no leakage of reaction product in the grafted tissue. A small percentage (one of eight) of 5-day animals showed isolated, patchy leakage, but no evidence of rejection of the neural graft. At 6 days all of the grafts showed evidence of leakage, and 71% of these grafts showed infiltration of lymphocytes. By 7-8 days extensive leakage of HRP and widespread infiltration of lymphocytes and macrophages were clearly evident. The present study demonstrates that blood-brain barrier breakdown is correlated closely with the sequence of immunological rejection of the graft. While these results confirm that a barrier exists in healthy neural transplants, they suggest that immunological factors should be considered in cases in which grafts are not protected by an intact barrier.

Animals↗
PubMed1989

Transplanted rat retinae do not project in a topographic fashion on the host tectum.

We report here that transplanted rat retinae do not project in a topographically organized fashion onto the host tectum. In fact, following the injection of two small non-overlapping regions of the host tectum, one with Fluorogold, the other with Rhodamine conjugated latex microspheres, groups of ganglion cells labelled with either dye are found interspersed throughout the ganglion cell layer of the retinal transplant. The absence of topography in the projections of transplanted retinae offers a new opportunity to examine the mechanisms which lead to topographically ordered projections in normal development.

Animals↗