Graft-versus-host disease impairs cerebellar growth

Griffin, W. Sue T.; Head, Judith R.; Woodward, Donald J.; Carrol, Clark L.

doi:10.1038/275315a0

Cited by 15 publications

(9 citation statements)

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“…The resulting disease has characteristic features including an altered gait (Billingham, 1968) reminiscent of cerebellar dysfunction. We have previously shown that the cerebellum of neonatal rats with GVHD is indeed altered morphologically and bioc hemically, without lymphocytic infiltration or inflammation of the cerebellum (Griffin et al, 1978;. Our experimental data in the rat suggest that GVHD inadvertently induced in children during periods of CNS development may give rise to abnormal development of brain regions in which cell proliferation is ongoing.…”

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confidence: 59%

“…In both humans and experimental animals, GVHD results from grafting immune-competent lymphoid cells into a tolerant host recipient that cannot recognize the "graft" as nonself, i.e., foreign, while the grafted cells do recognize the host's cells as foreign (Billingham et al, 1962). In the rat, this graft recognition of host cells as foreign results in the killing of host cells by grafted, cytotoxic T lymphocytes and decreased proliferation of germinal cells in vital organs such as heart (unpublished data) and brain (Griffin et al, 1978;.…”

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confidence: 94%

“…In rats, GVHD induced by allogeneic cell injection can be terminated by early treatment with alloantiserum (AAS) containing high titers of antibody directed against the allogeneic cell graft (Silvers and Billingham, 1969;Clancy and Rieki, 1973). Indeed, we have shown that the GVHDinduced decreases in Cerebellar DNA synthesis (Griffin et al, 1978), mitotic activity , and the number of newly formed cells (Griffin et al, 1979) are reversible if the disease is terminated by initiation of AAS treatment on day 11 (Griffin et al, 1982).…”

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confidence: 99%

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Normalization of Cerebellar RNA Synthesis and mRNA Levels After Treatment of Graft Versus Host Disease

Griffin

Snider

Morrison

1982

Journal of Neurochemistry

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We have previously shown that neonatal rats with graft versus host disease (GVHD) (1) synthesize significantly less cerebellar RNA, (2) have RNA that is less translationally active, and (3) have changes in the relative abundance of certain mRNAs, including the induction of one coding for protein r that is present neither in control cerebellum nor in other brain regions at any age. Here we report on the ability of the cerebellum to recover from GVHD-induced changes in the synthesis of total RNA and in the relative levels of specific mRNAs. In order to halt the disease, 11-day-old diseased Fischer animals were injected with hyperimmune alloantiserum daily for 3 days. Cytoplasmic RNAs were isolated from the cerebella of 14-day-old serum-treated animals, their diseased littermates that were not treated with serum, and littermate controls. Comparison, by two-dimensional gel analysis, of the in vitro synthesized mRNA translation products showed that most GVHD-induced alterations in the levels of specific mRNAs were not present in serum-treated animals. In particular, protein r was not synthesized by cerebellar RNAs isolated from serum-treated animals. These results show that the adverse effects of this disease are reversible at the molecular level.

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confidence: 59%

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confidence: 94%

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confidence: 99%

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Normalization of Cerebellar RNA Synthesis and mRNA Levels After Treatment of Graft Versus Host Disease

Griffin

Snider

Morrison

1982

Journal of Neurochemistry

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“…The remaining one-third of each litter served as controls. We previously determined that injection of either 40 X 106 syngeneic lymph node cells at birth (5) or 0.2 ml of alloantiserum on postnatal days [11][12][13] The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.…”

Section: Methodsmentioning

confidence: 99%

Manipulation of brain DNA synthesis is achieved by using a systemic immunological disease.

Griffin¹,

Crom²,

Head³

1982

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

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Previously, we showed that as early as postnatal day 11 an immunological disease, graft-versus-host disease, induced by grafting allogeneic lymph node cells into an immunoincompetent neonatal rat significantly decreases cerebellar histogenesis-i.e., DNA synthesis and the number of newly formed neurons. Here, we report that, subsequent to successful immunotherapy, there was a reversal of the deleterious graft-versushost disease-induced alterations in DNA synthesis in individual cerebellar germinal cells. Immunotherapy involved treating the diseased rats on postnatal days 11, 12, and 13 with alloantiserum specifically directed against the grafted lymph node cells injected on the day of birth. On postnatal day 14, diseased, serum-treated, and control littermates were injected with [3H]thymidine and, 15 min later, the cerebella were excised and autoradiographed. A 0.72-mm segment of the external granular layer in the cerebellar fissure between lobules VIB and C was searched for labeled cells. The control group had the greatest number-of labeled cells, defined by the presence of six or more autoradiographic grains, (43 + 4, mean ± SEM) and the greatest number of grains per cell (9.5 ± 0.2). Rats with the disease had few labeled cells (4 ± 2) and the number of grains per cell was low (6.6 ± 0.6); however, serum treatment increased both the number of labeled cells (26 ± 8) and the number of grains per cell (7.4 ± 0.2). These results show that without mononuclear infiltrates or inflammation in the cerebellum, a systemic immunological disease can dramatically decrease DNA synthesis per germinal cell and, moreover, that halting the disease by alloantiserum therapy can reverse this effect. These findings emphasize the sensitive plastic nature of neuronal cell acquisition in the normally developing brain.To determine the extent to which neural tissue can repair, by cellular proliferation, after a period ofarrested growth or injury, manipulation of DNA synthesis is necessary-i.e., a relatively rapid (a few days) suppression and subsequent restoration of DNA synthesis paralleled by a decrease and subsequent increase in the formation of identifiable neuronal cell types. Graft-versus-host disease (GVHD), which can be arrested by treatment of host animals with alloantiserum, provides such a manipulatory process (1). Because newborn rodents are not competent to recognize foreign tissues, immunocompetent allogeneic lymph node cells grafted on the day of birth (day 0) attack and destroy host lymphomyeloid cells, thus inducing the systemic immune syndrome, GVHD (2, 3). In the course of the disease, a decrease in cell proliferation in a number of vital organs occurs (4). Furthermore, an altered gait, suggestive ofcentral nervous system involvement, is known to be one of the manifestations of GVHD. The cerebellum is indeed one of the organs adversely affected by neonatally induced GVHD, as indicated by a dramatic decrease in DNA synthesis, by postnatal day 11, an event that precedes the wasting process characterizing the late...

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“…Further evidence that the immune system can damage the cerebellum, even in the absence of a pathogen, comes from graft-verses-host disease in the rat [250]. This was discovered by transplanting a cell-graft to pregnant rats which led to a systemic immune response.…”

Section: Discussionmentioning

confidence: 99%

Congenital LCMV virus

Licona¹,

Washington²

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Of a thesis on Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy severely injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection, as they develop neuropathology, including cerebellar injuries, similar to those seen in humans. The goal of this thesis was to determine what underlies brain injury and the differential immune response and to determine the role of T-cells in LCMV induced pathology. First, I examined whether cytokine and chemokine expression after LCMV infection was higher in the cerebellum and olfactory bulbs, which undergo destruction, compared to the hippocampus and septum, which undergo no acute destruction. Second, I used T-cell deficient and T-cell competent animals to evaluate the role of T-lymphocytes in LCMV-induced cerebellar and hippocampus pathology. Finally, I characterized the migration abnormality that develops in the cerebellum after LCMV infection. My results showed that cytokine and chemokine expression is higher in the cerebellum and olfactory bulb than in the hippocampus and septum. Using astrocyte cultures, I determined that astrocytes isolated from the cerebellum have a more robust cytokine response to infection compared to astrocytes from the hippocampus. Furthermore, inoculation of congenitally athymic (rnu/rnu) rats, which are deficient in T-lymphocytes, demonstrated that cerebellar hypoplasia is T-cell independent while cerebellar destruction and abnormal neuron migration is T-cell dependent. In the hippocampus, T-cells protect against loss of dentate granule cells. A study of the migration abnormality determined that LCMV infection disrupts radial glia fibers and extends proliferation of granule cells in a T-cell dependent manner. The findings reported here support a pivotal role of the immune system in regional brain pathology as well as in the disruption of migration. To my family and friends for their help and support during my research time and thesis document preparation. To my beloved husband, Humberto, and my little girls Gloria and Isabel who provided me with emotional and intellectual support during my thesis research and watched me tirelessly while I worked towards this degree. To my parents, David and Elizabeth, and my siblings, Zachariah, Rebekah, Nich, Valerie, Kevin, Caitlin, Thomas, and Emily, who tenderly cared for my children during the long days when my research occupied my mental and physical might. And lastly, to my fellow lab mates and advisors, Jo Mahoney, Glenda Rabe, Arya Ordoubadian, Shenglan Li, Bahri Karacay, and Daniel J Bonthius, who taught me many techniques, helped me with experiments, and aided me in my scientific and intellectual growth throughout my PhD years. ii ACKNOWLEDGMENTS First, I would like to acknowledge the Neuroscience Program and the NINDS F31 fellowship or funding my PhD training. I would like to acknowledge my thesis committee, Daniel J. Bonthius (chair), Joshua Weiner, Robert Cornell, Stanley Perlman, Charles Grose, and Michael Dailey, for their in...

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Graft-versus-host disease impairs cerebellar growth

Cited by 15 publications

References 15 publications

Normalization of Cerebellar RNA Synthesis and mRNA Levels After Treatment of Graft Versus Host Disease

Normalization of Cerebellar RNA Synthesis and mRNA Levels After Treatment of Graft Versus Host Disease

Manipulation of brain DNA synthesis is achieved by using a systemic immunological disease.

Congenital LCMV virus

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