Systemic Immune Deficiency Necessary for Cytomegalovirus Invasion of the Mature Brain

Reuter, Jon D.; Gomez, Daniel L.; Wilson, Judith; Pol, Anthony N. van den

doi:10.1128/jvi.78.3.1473-1487.2004

Cited by 48 publications

(49 citation statements)

References 42 publications

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“…As we demonstrate, viral clearance in BALB/c mice is expedited through prior exposure to virus and activation of lymphocytes. Neurons are also permissive to MCMV infection in the mature brain (54), and as our data show, adoptive therapy completely cleared active infection from all cells of the CNS, suggesting an important role for T cells in control of CMV infection in the brain. MHC expression in neurons is variable (31,42,49), T-cell-induced viral clearance mechanisms from these cells may differ from those in other organs.…”

Section: Discussionmentioning

confidence: 68%

“…Reconstitution of SCID mice with either MCMV-immune cells or naïve splenocytes provided for a strong protective response within the brain against CMV following systemic virus challenge. No adverse clinical signs of disease were seen throughout the entire study in reconstituted mice of both groups, unlike the nonreconstituted SCID control mice that did show significant viral proliferation and after 21 days begin to develop clinical signs of hunched posturing, scruffy hair coat, and lethargy (54).…”

Section: Downloaded Frommentioning

confidence: 97%

“…Peripheral inoculation with MCMV results in invasion of the brain within 3 weeks in SCID mice, whereas immunocompetent controls show no CMV in the brain (54). Extending results from experiments directed at testing the efficacy of adoptive reconstitution for treatment of acute neurotropic disease, we postulated that adoptive transfer could also prevent dissemination of peripheral MCMV infection to brains of immunodeficient mice.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Mice were assessed daily for adverse clinical signs and virus quantification was performed after 28 days. Serum MCMV antibody levels were assessed using indirect fluorescent antibody staining using previously described polyclonal anti-MCMV sera (54).…”

Section: Methodsmentioning

confidence: 99%

“…MCMV behaves similar to human CMV by entering the brain only in immunodeficient individuals, infecting multiple cell types, causing pathology, and the absence of functional immunity, progressing to lethality (54). We employed MCMV as a paradigm in studies aimed at developing treatment against the virus.…”

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CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

Reuter¹,

Wilson²,

Idoko³

et al. 2005

J Virol

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Cytomegalovirus (CMV) infection is the most common opportunistic infection of the central nervous systemin patients with human immunodeficiency virus or AIDS or on immunosuppressive drug therapy. Despite medical management, infection may be refractory to treatment and continues to cause significant morbidity and mortality. We investigated adoptive transfer as an approach to treat and prevent neurotropic CMV infection in an adult immunodeficient mouse model. SCID mice were challenged with intracranial murine CMV (MCMV) and reconstituted with MCMV-or vesicular stomatitis virus (VSV)-sensitized splenocytes, T cells, or T-cell subsets. T cells labeled with vital dye or that constitutively generated green fluorescent protein (GFP) were identified in the brain as early as 3 days following peripheral transfer. Regardless of specificity, activated T cells localized to regions of the brain containing CMV, however, only those specific for CMV were effective at clearing virus. Reconstitution with unsorted MCMV-immune splenocytes, enriched T-cell fractions, or CD4؉ cells significantly reduced virus levels in the brain within 7 days and also prevented clinical disease, in significant contrast with mice given VSV-immune unsorted splenocytes, MCMV-immune CD8 ؉ T cells, and SCID control mice. Results suggest CMV-immune T cells (particularly CD4 ؉ ) rapidly cross the blood-brain barrier, congregate at sites of specific CMV infection, and functionally eliminate acute CMV within the brain. In addition, when CMV-immune splenocytes were administered prior to a peripheral CMV challenge, CMV entry into the immunocompromised brain was prevented. Systemic adoptive transfer may be a rapid and effective approach to preventing CMV entrance into the brain and for reducing neurotropic infection.

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Section: Discussionmentioning

confidence: 68%

Section: Downloaded Frommentioning

confidence: 97%

Section: Downloaded Frommentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

Reuter¹,

Wilson²,

Idoko³

et al. 2005

J Virol

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Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

et al. 2011

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Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Because of the presence of multiple leptin/receptor (ObR) interaction sites and diverse leptin activities, the literature lacks truly monofunctional leptin protein derivatives or fragments. To date, selective ObR antagonists have not been reported. We developed short, pharmacologically advantageous peptide analogs of ObR-binding site III of leptin that acted as selective ObR inhibitors without any partial agonistic activity. These reduced leptin-dependent growth and signaling in cancer cell lines at picomolar and low nanomolar concentrations. In immunocompromised mice the peptides suppressed the growth of rapidly proliferating orthotopic human breast cancer xenografts by 50% when administered either intraperitoneally (i.p.) or subcutaneously (s.c.) for 38 days at a 0.1 mg/kg/day dose. The peptides were distributed to the brain, and when added to growing C57BL/6 normal mice i.p., s.c., or orally, the lead antagonist accelerated normal weight increase without producing any toxic effects. Weight gain increases could not be observed after 10-12 days of treatment indicating that the mice became resistant to the central nervous system activity of leptin antagonists. However, in normal growing rats the intranasal administration at 0.1 mg/kg/day for 20 days resulted in a 2% net total body weight gain without signs of resistance induction. In addition to the potential of these peptides in drug development against primary and metastatic tumors and cachexia, our data confirm that resistance to leptin resides at the blood-brain barrier.

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Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines

Boppana

Britt

2021

Methods in Molecular Biology

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Systemic Immune Deficiency Necessary for Cytomegalovirus Invasion of the Mature Brain

Cited by 48 publications

References 42 publications

CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines

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Systemic Immune Deficiency Necessary for Cytomegalovirus Invasion of the Mature Brain

Cited by 48 publications

References 42 publications

CD4+T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

CD4+T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines

Contact Info

Product

Resources

About

CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain