Background: Bone marrow mesenchymal stem cells (bmMSC) may play a role in the regulation of maturation, proliferation, and functional activation of lymphocytes, though the exact mechanisms are unknown. MSC-derived exosomes induce a regulatory response in the function of B, T, and monocyte-derived dendritic cells. Here, we evaluated the specific inhibition of human lymphocytes by bmMSC-derived exosomes and the effects on B-cell function.Methods: Exosomes were isolated from culture media of bmMSC obtained from several healthy donors. The effect of purified bmMSC-derived exosomes on activated peripheral blood mononuclear cells (PBMCs) and isolated B and T lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester assay. Using the Illumina sequencing platform, mRNA profiling was performed on B-lymphocytes activated in the presence or absence of exosomes. Ingenuity® pathway analysis software was applied to analyze pathway networks, and biological functions of the differentially expressed genes. Validation by RT-PCR was performed. The effect of bmMSC-derived exosomes on antibody secretion was measured by ELISA.Results: Proliferation of activated PBMCs or isolated T and B cells co-cultured with MSC-derived exosomes decreased by 37, 23, and 18%, respectively, compared to controls. mRNA profiling of activated B-lymphocytes revealed 186 genes that were differentially expressed between exosome-treated and control cells. We observed down- and up-regulation of genes that are involved in cell trafficking, development, hemostasis, and immune cell function. RNA-Seq results were validated by real time PCR analysis for the expression of CXCL8 (IL8) and MZB1 genes that are known to have an important role in immune modulation. Functional alterations were confirmed by decreased IgM production levels. Consistent results were demonstrated among a wide variety of healthy human bmMSC donors.Conclusion: Our data show that exosomes may play an important role in immune regulation. They inhibit proliferation of several types of immune cells. In B-lymphocytes they modulate cell function by exerting differential expression of the mRNA of relevant genes. The results of this study help elucidate the mechanisms by which exosomes induce immune regulation and may contribute to the development of newer and safer therapeutic strategies.

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The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.

Bone marrow transplantation (BMT) to treat severe hematologic malignancies often leads to potentially fatal acute graft-versus-host disease (GVHD), despite attempts at better donor-recipient matching and/or use of immunosuppressive agents. We report that embryo-derived PreImplantation Factor (PIF) plays a determining role in developing maternal/host tolerance toward the semiallogeneic or total allogeneic embryo and in regulating systemic immune response. Synthetic PIF treatment has proven effective in preventing immune attacks in nonpregnant models of autoimmunity. In this study, we tested the capability of PIF to prevent the development of acute GVHD in semiallogeneic or totally allogeneic murine BMT models. We examined the regulatory effect of PIF both in vivo and in vitro to control deleterious GVHD while maintaining its ability to preserve the beneficial graft-versus-leukemia (GVL) effect. Bone marrow and spleen cells from C57BL/6 donors were transplanted in semiallogeneic (C57BL/6xBALB/c) F1 or allogeneic (BALB/c) mice, which were then treated with PIF 1 mg/kg/day for 2 weeks. Short-term PIF administration reduced acute GVHD in both models and increased survival for up to 4 months after semiallogeneic or totally allogeneic BMT. This effect was coupled with decreased skin inflammation (semiallogeneic model) and decreased liver inflammation (both models), as well as reduced colon ulceration (allogeneic model). GVHD-associated cytokine and chemokine gene expression were decreased in the liver. PIF further lowered circulating IL-17 levels, but not IFN-γ levels. Both in vivo and in vitro, PIF treatment was demonstrated to lead to decreased inducible nitric oxide synthase expression and decreased lipopolysaccharide-activated macrophages to lower nitric oxide secretion. Significantly, PIF did not diminish the beneficial GVL effect in the B cell leukemia model. PIF acts primarily by inducing the regulatory phenotype on monocytes/antigen-presenting cells, which controls T cell proliferation. Overall, our data demonstrate that PIF protects against semiallogeneic and allogeneic GVHD long term by reducing both target organ and systemic inflammation and by decreasing oxidative stress, while preserving the beneficial GVL effect.