Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity.

In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), relapses are markedly reduced during pregnancy. Exosomes are lipid-bound vesicles and are more abundant in the serum during pregnancy. Using murine EAE, we demonstrate that serum exosomes suppress T cell activation, promote the maturation of oligodendrocyte precursor cells (OPC), and pregnancy exosomes facilitate OPC migration into active CNS lesions. However, exosomes derived from both pregnant and non-pregnant mice reduced the severity of established EAE. Thus, during pregnancy, serum exosomes modulate the immune and central nervous systems and contribute to pregnancy-associated suppression of EAE.

Anti-angiogenic gene therapy in the treatment of malignant gliomas.

More than four decades ago, Dr. Judah Folkman hypothesized that angiogenesis was a critical process in tumor growth. Since that time, there have been significant advances in understanding tumor biology and groundbreaking research in cancer therapy that have validated his hypothesis. However, in spite of extensive research, glioblastoma multiforme (GBM), the most common and malignant primary brain tumor, has gained little in the way of improved median survival. There have been several angiogenesis targets that have resulted in drugs that are in clinical trials or FDA approved for clinical use in several cancers. GBM is a highly angiogenic tumor and several drugs are showing promise in clinical trials with one (bevacizumab), clinically approved for use. We will review several possible angiogenic targets in GBM as well as the vector methodologies used for delivery. In addition, GBMs present several therapeutic challenges related to structure, tumor immune microenvironment and resistance to angiogenesis. To overcome these challenges will require novel approaches to improve therapeutic gene expression and vector biodistribution in the glioma.

Extracellular vesicles and their convergence with viral pathways.

Extracellular vesicles (microvesicles), such as exosomes and shed microvesicles, contain a variety of molecules including proteins, lipids, and nucleic acids. Microvesicles appear mostly to originate from multivesicular bodies or to bud from the plasma membrane. Here, we review the convergence of microvesicle biogenesis and aspects of viral assembly and release pathways. Herpesviruses and retroviruses, amongst others, recruit several elements from the microvesicle biogenesis pathways for functional virus release. In addition, noninfectious pleiotropic virus-like vesicles can be released, containing viral and cellular components. We highlight the heterogeneity of microvesicle function during viral infection, addressing microvesicles that can either block or enhance infection, or cause immune dysregulation through bystander action in the immune system. Finally, endogenous retrovirus and retrotransposon elements deposited in our genomes millions of years ago can be released from cells within microvesicles, suggestive of a viral origin of the microvesicle system or perhaps of an evolutionary conserved system of virus-vesicle codependence. More research is needed to further elucidate the complex function of the various microvesicles produced during viral infection, possibly revealing new therapeutic intervention strategies.

Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors.

Multiple sclerosis (MS) is a demyelinating disease of the CNS involving T cell targeting of myelin antigens. During pregnancy, women with MS experience decreased relapses followed by a post partum disease flare. Using murine experimental autoimmune encephalomyelitis, we recapitulate pregnancy findings in both relapsing and progressive models. Pregnant mice produced less TNF-α, IL-17 and exhibited reduced CNS pathology relative to non-pregnant controls. Microparticles, called exosomes, shed into the blood during pregnancy were isolated and found to significantly suppress T cell activation relative to those from non-pregnant controls. These results demonstrate the immunosuppressive potential of pregnancy and serum-derived pregnancy exosomes.

Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production.

Women with multiple sclerosis (MS) often experience a decrease in relapse rate during pregnancy, most notably during the third trimester, with a flare of disease activity 3-6 mo postpartum. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have shown that pregnancy delays the onset and decreases the incidence of disease. We investigated the effect of pregnancy and the postpartum period in a remitting-relapsing model of murine EAE. When immunization occurs during pregnancy, mice show a reduction in the incidence of EAE as well as a decrease in clinical severity, while mice immunized during the postpartum period exhibit more severe disease. No differences in lymphocyte proliferation or expression of activation markers were noted when immunization occurred during pregnancy as compared with the nonpregnant controls. Mice immunized during pregnancy produced less TNF-alpha and IL-17, and showed an increased number of IL-10-secreting cells within the CD11b+, CD11c+, CD19+, and CD4+/CD25+ populations. No differences were noted in the production of IFN-gamma, IL-2, IL-4, and IL-5. These results suggest that when an Ag is introduced during pregnancy, an immunoregulatory rather than an immunosuppressive or Th2 environment predominates.