1. Cell-Autonomous Processes That Impair Xenograft Survival into the Cerebellum
Lorenzo Magrassi, Giulia Nato, Domenico Delia, Annalisa Buffo Cerebellum. 2022 Oct;21(5):821-825. doi: 10.1007/s12311-022-01414-3. Epub 2022 May 16.
In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft.
2. Genetic forms of neurohypophyseal diabetes insipidus
Jonas Rutishauser, Martin Spiess, Peter Kopp Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):249-62. doi: 10.1016/j.beem.2016.02.008. Epub 2016 Feb 18.
Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro. In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II (AVP) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin (WFS 1) gene.
3. Cadmium-induced immunotoxicity
K J Stelzer, T L Pazdernik Int J Immunopharmacol. 1983;5(6):541-8. doi: 10.1016/0192-0561(83)90047-4.
This study assessed the effects of cadmium on functional lymphopoietic precursor cells and cell size in both spleen and bone marrow. Splenic plaque-forming cell (S-PFC) precursors were stimulated by a thymus independent immunogen (TNP-LPS) and by a thymus dependent immunogen (TNP-BSA plus dextran sulfate). Bone marrow plaque-forming cell (M-PFC) precursors were stimulated by TNP-LPS plus dextran sulfate. Male C57Bl/6J mice received either a single ip injection of 5.9 mg/kg CdCl2, and were sacrificed 3 days later (ip group), or 5 daily sc injections of 3.26 mg/kg CdCl2, and were sacrificed either 2 days later (7 day sc group) or 7 days later (12 day sc group). The ip group showed an increase in spleen cellularity which resulted in an enhanced S-PFC (TNP-LPS) response per spleen and compensated for a depressed S-PFC (TNP-BSA) response per 10(6) cells cultured. Bone marrow cellularity was not significantly decreased but the M-PFC response was drastically depressed. Similar results were obtained in the 7 day sc group. However, a significant increase in spleen cellularity was not seen, resulting in a noncompensated decrease in S-PFC (TNP-BSA) response. The S-PFC (TNP-LPS) response per 10(6) cells cultured was increased in this group. Responses were similar to controls in the 12 day sc group, but bone marrow cellularity was decreased. The ip and 7 day sc groups showed substantial cadmium-induced shifts in bone marrow cell size distribution profile to larger diameters. Changes in spleen cell size distribution were not as significant. Partial recovery was evident in the 12 day sc group. This study demonstrated that in vivo exposure to cadmium has a greater effect on the in vitro function of immature B-cells in the bone marrow than on more mature B-cells found in the spleen.(ABSTRACT TRUNCATED AT 250 WORDS)
