Dataset Information

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

ABSTRACT: Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical.We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents.Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known.Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

SUBMITTER: Hippen KL

PROVIDER: S-EPMC5175408 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

Hippen Keli L KL Watkins Benjamin B Tkachev Victor V Lemire Amanda M AM Lehnen Charles C Riddle Megan J MJ Singh Karnail K Panoskaltsis-Mortari Angela A Vanhove Bernard B Tolar Jakub J Kean Leslie S LS Blazar Bruce R BR

Transplantation 20161201 12

<h4>Background</h4>Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better unders ...[more]

PMID: 27861291

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Project description:IntroductionThe gray mouse lemur (Microcebus murinus) is an important nonhuman primate model in biomedical research. Numerous studies investigated mouse lemur behavior and possible factors underlying interindividual variation in both, animal personality and cognitive performance. Some effects, such as an age-related decline in executive functioning, have robustly been found across laboratory colonies; however, little is known about the brain structural substrates in mouse lemurs.MethodsHere, we provide first exploratory data linking in vivo magnetic resonance imaging of 34 mouse lemurs to performance in a standardized, touchscreen-based task on object discrimination and reversal learning as well as to animal personality under different scenarios in an open field.ResultsHigh interindividual variability in both brain morphometric and behavioral measurements was found, but only few significant correlations between brain structure and behavior were revealed: Object discrimination learning was linked to the volume of the hippocampus and to temporal lobe thickness, while reversal learning was linked to thalamic volume and the thickness of the anterior cingulate lobe. Emergence latency into the open field correlated with volume of the amygdala. General exploration-avoidance in the empty open-field arena correlated with thicknesses of the anterior cingulate lobe and fronto-parietal substructures. Neophilia, assessed as exploration of a novel object placed in the arena, among others, related to the volume of the caudate nucleus.ConclusionIn summary, our data suggest a prominent role of temporal structures (including the hippocampus) for learning capability, as well as thalamic and anterior cingulate structures for cognitive flexibility and response inhibition. The amygdala, the anterior cingulate lobe, and the caudate nucleus are particularly linked to animal personality in the open-field setting. These findings are congruent with the comparative psychological literature and provide a valuable basis for future studies elucidating aspects of behavioral variation in this nonhuman primate model.

Project description:Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.

Dataset Information

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

Publications

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

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