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9. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis

Author

Oria Alonso, Marc, Duru, Soner, Figueira, Rebeca L., Scorletti, Federico, Turner, Lucas E., Fernandez-Alonso, Irati, Fernandez-Martin, Alejandra, Marotta, Mario, Sbragia, Lourenco, Shaaban, Aimen F., Peiro, Jose L., Universitat Autònoma de Barcelona, Oria Alonso, Marc, Duru, Soner, Figueira, Rebeca L., Scorletti, Federico, Turner, Lucas E., Fernandez-Alonso, Irati, Fernandez-Martin, Alejandra, Marotta, Mario, Sbragia, Lourenco, Shaaban, Aimen F., Peiro, Jose L., and Universitat Autònoma de Barcelona

Abstract

Exencephaly/anencephaly is one of the leading causes of neonatal mortality and the most extreme open neural tube defect with no current treatments and limited mechanistic understanding. We hypothesized that exencephaly leads to a local neurodegenerative process in the brain exposed to the amniotic fluid as well as diffuse degeneration in other encephalic areas and the spinal cord. To evaluate the consequences of in utero neural tissue exposure, brain and spinal cord samples from E17 exencephalic murine fetuses (maternal intraperitoneal administration of valproic acid at E8) were analyzed and compared to controls and saline-injected shams (n = 11/group). Expression of apoptosis and senescence genes (p53, p21, p16, Rbl2, Casp3, Casp9) was determined by qRT-PCR and protein expression analyzed by western blot. Apoptosis was measured by TUNEL assay and PI/AV flow cytometry. Valproic acid at E8 induced exencephaly in 22% of fetuses. At E17 the fetuses exhibited the characteristic absence of cranial bones. The brain structures from exencephalic fetuses demonstrated a loss of layers in cortical regions and a complete loss of structural organization in the olfactory bulb, hippocampus, dental gyrus and septal cortex. E17 fetuses had reduced expression of NeuN, GFAP and Oligodendrocytes in the brain with primed microglia. Intrinsic apoptotic activation (p53, Caspase9 and 3) was upregulated and active Caspase3 localized to the layer of brain exposed to the amniotic fluid. Senescence via p21-Rbl2 was increased in the brain and in the spinal cord at the lamina I-II of the somatosensory dorsal horn. The current study characterizes CNS alterations in murine exencephaly and demonstrates that degeneration due to intrinsic apoptosis and senescence occurs in the directly exposed brain but also remotely in the spinal cord.

Published
2019

10. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis

Author

Oria, Marc, primary, Duru, Soner, additional, Figueira, Rebeca L., additional, Scorletti, Federico, additional, Turner, Lucas E., additional, Fernandez-Alonso, Irati, additional, Fernandez-Martin, Alejandra, additional, Marotta, Mario, additional, Sbragia, Lourenco, additional, Shaaban, Aimen F., additional, and Peiro, Jose L., additional

Published
2019
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14. Mechanisms by which chronic ethanol feeding limits the ability of dendritic cells to stimulate T cell proliferation

Author

Fan, Ji, Edsen-Moore, Michelle R., Turner, Lucas E., Cook, Robert T., Legge, Kevin L., Waldschmidt, Thomas J., and Schlueter, Annette J.

Subjects
Antigen Presentation, Time Factors, Ethanol, T-Lymphocytes, Cell Differentiation, Dendritic Cells, Lymphocyte Activation, Article, Receptors, Tumor Necrosis Factor, Rats, Mice, Inbred C57BL, Alcoholism, Disease Models, Animal, Mice, Antigens, CD, Cricetinae, Toll-Like Receptor 9, Animals, Cytokines, Female, Spleen
Abstract

As initiators of immune responses, dendritic cells (DCs) are required for antigen (Ag)-specific activation of naïve T cells in the defense against infectious agents. The increased susceptibility to and severity of infection seen in chronic alcoholics could be because of impaired DCs initiation of naïve T-cell responses. Specifically, these DCs may not provide adequate Signals 1 (Ag presentation), 2 (costimulation), or 3 (cytokine production) to these T cells.Using the Meadows-Cook murine model of chronic alcohol abuse, the ability of ethanol (EtOH)-exposed DCs to stimulate T-cell proliferation, acquire and process Ag, express costimulatory molecules, and produce inflammatory cytokines was assessed.Normal naïve T cells primed by EtOH-exposed DCs showed decreased proliferation in vitro and in vivo, compared to water-fed control mice. These EtOH-exposed DCs, after activation by CpG or tumor necrosis factor alpha (TNFα), were less able to upregulate costimulatory molecules CD40, CD80, or CD86, and produced less IL-12 p40, TNFα, and IFNα than DCs from water-fed mice. TLR9 and TNF receptor expression were also reduced in/on EtOH-exposed DCs. No evidence of defective Ag acquisition or processing as a result of EtOH feeding was identified.Inadequate proliferation of normal T cells following stimulation by EtOH-exposed DCs is likely a result of diminished Signal 2 and Signal 3. Lack of adequate inflammatory stimulation of EtOH-exposed DCs because of diminished receptors for inflammatory mediators appears to be at least partially responsible for their dysfunction. These findings provide a mechanism to explain increased morbidity and mortality from infectious diseases in alcoholics and suggest targets for therapeutic intervention.

Published
2010

21. A Practical Method of Chronic Ethanol Administration in Mice.

Author

Walker, John, Cherry, Mark J., Coleman, Ruth A., Young, Betty M., Turner, Lucas E., and Cook, Robert T.

Abstract

Mice provide a useful model for the study of immune deficiency caused by chronic alcohol abuse. Their suitability is related to several factors, including in particular the extensive knowledge base in the immunology of mice already existing in the literature. Specific modeling of the immunodeficiency of the chronic human alcoholic requires that ethanol must be administered to the model for a significant portion of its life span. In mice, it has proven to be necessary to administer ethanol daily for up to 32 wk or longer to observe all the immune abnormalities that occur in middle-aged alcoholic humans. Such time spans are problematic with many of the common protocols for ethanol administration. It has been shown by others and confirmed by our group that the most practical way of accomplishing such long protocols is by administering ethanol in water as the only choice of water. Details of management of the chronic ethanol mouse colony are described here that are necessary for the success of such studies, including methods for initiating ethanol administration, maintenance of barrier protection, monitoring weight gain, strain differences and fetal alcohol exposure. [ABSTRACT FROM AUTHOR]

Published
2008
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22. Chronic ethanol induces inhibition of antigen‐specific CD8+but not CD4+immunodominant T cell responses following Listeria monocytogenesinoculation

Author

Gurung, Prajwal, Young, Betty M., Coleman, Ruth A., Wiechert, Susan, Turner, Lucas E., Ray, Nancy B., Waldschmidt, Thomas J., Legge, Kevin L., and Cook, Robert T.

Abstract

Chronic ethanol consumption results in immunodeficiency. Previous work with chronic ethanol‐fed mice has shown reduced splenic weight and cellularity, including reduced numbers of CD8+T cells. However, antigen‐specific CD8+and CD4+T cell responses in chronic ethanol‐fed mice have been studied relatively little. We have used an attenuated Listeria monocytogenesstrain DPL 1942 (LM ΔactA) to inoculate mice and subsequently used CD4+and CD8+immunodominant peptides of LM to measure the CD4+and CD8+T cell responses after chronic ethanol exposure. We found no major differences between control and ethanol‐fed mice in the kinetics and persistence of antigen‐specific CD4+T cells in response to an immunodominant LM peptide, as measured by intracellular IFN‐γ staining. In contrast to CD4+responses, three methods of in vitro antigen presentation indicated that the primary response of CD8+T cells to several different epitopes was reduced significantly in mice chronically fed ethanol. Antigen‐specific CD8+T cells were also reduced in chronic ethanol‐fed mice during the contraction phase of the primary response, and memory cells evaluated at 29 and 60 days after inoculation were reduced significantly. BrdU proliferation assays showed that in vivo proliferation of CD8+T cells was reduced in ethanol‐fed mice, and IL‐2‐dependent in vitro proliferation of naive CD8+T cells was also reduced. In conclusion, these results suggest that antigen‐specific CD4+T cell responses to LM are affected little by chronic ethanol consumption; however, antigen‐specific CD8+T cell responses are reduced significantly, as are in vivo and in vitro proliferation. The reduction of antigen‐specific CD8+T cells may contribute strongly to the immunodeficiency caused by ethanol abuse.

Published
2009
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23. Absorption After Neural Tube Teratogenesis is Dependent on Maternal Immune Cell Function

Author

Ott, Katherine C., Marc Oria, Redden, Catherine R., Kang, Hee Kap, Skital, Veronica, Turner, Lucas E., Alhajjat, Amir A., Duru, Soner, Peiro, Jose L., and Shaaban, Aimen F.

Subjects
Immunology, Immunology and Allergy
Abstract

Introduction: Neural tube defects (NTDs), are severe malformations of the developing central nervous system. After having a pregnancy affected by NTD, the recurrence risk increases 20x. The predisposition to having children affected by NTDs has not been explained and may relate to surveillance by the maternal immune system as maternal immune cells such as NK and T cells have been shown to traffic in the fetal circulation. We hypothesized that maternal NK and T cells are necessary for selective fetal absorption after the development of an NTD. Methods: We challenged this hypothesis in an outbred murine model of valproic acid (VA)-induced fetal neural tube teratogenesis (NTT) performed of pregnant CD1 dams at E8. To evaluate protection from NTTs, maternal NK cells were selectively eliminated (mAb PK136) on E7. Maternal CD4+ and CD8+ T cells were selectively eliminated (GK1.5 and 2.43) on E6. All litters were harvested on E14 and prevalence of NTT compared between each treatment group and untreated controls. Results: The frequency of litters with VA-induced NTT was significantly higher when maternal NK cells or maternal T cells were selectively depleted compared to controls (100% and 88.2% vs 80.0%, p Conclusion: These findings demonstrate that selective fetal absorption for NTT is dependent on intact maternal immune cell function. Further studies are needed to define the roles that maternal NK and T cells have in the absorption process during abnormal development.

24. Prenatal Allospecific Tolerance Is Characterized By Early TregExpansion and a Surprisingly Slow Pace for TeffClonal Deletion

Author

Strong, Beverly SI, Lee, Amanda E, Newkold, Tess J, Turner, Lucas E, and Shaaban, Aimen F

Abstract

Prenatal transplantation capitalizes on the unique fetal environment, allowing for life-long engraftment of allogeneic stem cells without the need for harsh conditioning regimens. A prerequisite for stable engraftment of allogeneic cells likely requires the negative selection of donor-specific host effector T cells (Teff) and the support of donor-specific regulatory T cells (Tregs). However, little is known about the interplay between these cell types during development. The purpose of this study was to characterize the dynamic relationship between donor-specific Teffand Tregsas they emerge during development.

Published
2015
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25. Chronic ethanol induces inhibition of antigen-specific CD8+ but not CD4+ immunodominant T cell responses following Listeria monocytogenes inoculation.

Author

Gurung P, Young BM, Coleman RA, Wiechert S, Turner LE, Ray NB, Waldschmidt TJ, Legge KL, and Cook RT

Subjects
Animals, Antigen Presentation, Antigens, Bacterial immunology, CD8-Positive T-Lymphocytes pathology, Cell Proliferation, Cells, Cultured, Cytokines biosynthesis, Female, Interferon-gamma immunology, Interferon-gamma physiology, Listeria monocytogenes immunology, Listeriosis pathology, Lymphocyte Activation, Mice, Mice, Inbred BALB C, T-Lymphocytes, Cytotoxic immunology, Th2 Cells immunology, Alcohol Drinking immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Ethanol pharmacology, Listeria monocytogenes physiology, Listeriosis immunology
Abstract

Chronic ethanol consumption results in immunodeficiency. Previous work with chronic ethanol-fed mice has shown reduced splenic weight and cellularity, including reduced numbers of CD8+ T cells. However, antigen-specific CD8+ and CD4+ T cell responses in chronic ethanol-fed mice have been studied relatively little. We have used an attenuated Listeria monocytogenes strain DPL 1942 (LM DeltaactA) to inoculate mice and subsequently used CD4+ and CD8+ immunodominant peptides of LM to measure the CD4+ and CD8+ T cell responses after chronic ethanol exposure. We found no major differences between control and ethanol-fed mice in the kinetics and persistence of antigen-specific CD4+ T cells in response to an immunodominant LM peptide, as measured by intracellular IFN-gamma staining. In contrast to CD4+ responses, three methods of in vitro antigen presentation indicated that the primary response of CD8+ T cells to several different epitopes was reduced significantly in mice chronically fed ethanol. Antigen-specific CD8+ T cells were also reduced in chronic ethanol-fed mice during the contraction phase of the primary response, and memory cells evaluated at 29 and 60 days after inoculation were reduced significantly. BrdU proliferation assays showed that in vivo proliferation of CD8+ T cells was reduced in ethanol-fed mice, and IL-2-dependent in vitro proliferation of naive CD8+ T cells was also reduced. In conclusion, these results suggest that antigen-specific CD4+ T cell responses to LM are affected little by chronic ethanol consumption; however, antigen-specific CD8+ T cell responses are reduced significantly, as are in vivo and in vitro proliferation. The reduction of antigen-specific CD8+ T cells may contribute strongly to the immunodeficiency caused by ethanol abuse.

Published
2009
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