Biomedical subjects

Doina Ganea

Publications and source records attributed to Doina Ganea.

At least 19 recordsLinked to original sources

PubMed2006

Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease.

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by, and binding to, immune cells. Crohn's disease is a chronic debilitating disease characterized by severe T helper 1 (Th1)-driven inflammation of the gastrointestinal tract. The aim of this study is to investigate the therapeutic effect of cortistatin in a murine model of colitis. Cortistatin treatment significantly ameliorated the clinical and histopathologic severity of the inflammatory colitis, abrogating body weight loss, diarrhea, and inflammation and increased the survival rate of the colitic mice. The therapeutic effect was associated with down-regulation of inflammatory and Th1-driven autoimmune response, including the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect was demonstrated. Importantly, cortistatin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. This work identifies cortistatin as an antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, cortistatin represents a multistep therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.

Animals↗

PubMed2006

Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response.

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) that induce the generation/activation of regulatory T (Tr) cells for the treatment of acute GVHD following allogeneic BMT has been recently established. Therefore, the identification of factors that contribute to the development of tolerogenic DCs is highly relevant. We report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide (VIP), as a new approach to induce tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated in the presence of VIP impair allogeneic haplotype-specific responses of donor CD4(+) cells in mice given transplants by inducing the generation of Tr cells in the graft. VIP-induced tolerogenic DCs did not abrogate the graft-versus-leukemia response presumably by not affecting the cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DCs in future therapeutic regimens may minimize the dependence on nonspecific immunosuppressive drugs used currently as antirejection therapy, and facilitate the successful transplantation from mismatched donors, by reducing the deleterious consequences of acute GVHD and extending the applicability of BMT.

Acute Disease↗

PubMed2006

Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells.

Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (T(reg)) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 T(reg) cells from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature after the effects of inflammatory stimuli. CD4 T(reg) cells generated with VIP-differentiated DCs resemble the previously described Tr1 cells in terms of phenotype and cytokine profile. CD8 T(reg) cells generated with tolerogenic VIP DCs have increased numbers of IL-10-producing CD8(+)CD28(-)-CTLA4(+) T cells. CD4 and CD8 T(reg) cells primarily suppress antigen-specific T(H)1-mediated responses. Therefore, the possibility of generating or expanding ex vivo tolerogenic DC(VIPs) opens new therapeutic perspectives for treating autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.

Autoimmunity↗

PubMed2006

Granzyme B, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in Th2 but not Th1 effectors.

Following antigenic stimulation and differentiation, Th1 and Th2 effector cells contribute differently to cellular and humoral immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. In this study, we investigate the mechanisms for the protective effect of VIP against activation-induced cell death (AICD) of Th2 effectors. Surprisingly, microarray and protein data indicate that VIP prevents the up-regulation of granzyme B (GrB) in Th2 but not Th1 effectors. This is the first report of GrB expression in Th cells and of its involvement in activation-induced apoptosis. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors. The effect of VIP on Th2 survival and GrB expression is mediated through the VIP receptors 1 and 2 and cAMP signaling through exchange protein activated by cAMP and, to a lesser degree, protein kinase A. In addition to effects on GrB, VIP also down-regulates Fas ligand (FasL) and perforin (Pfr) expression. The extrinsic Fas/FasL pathway and the intrinsic GrB-dependent pathway act independently in inducing AICD. The mechanisms by which GrB induces cell death in Th1/Th2 effectors include both fratricide and suicide. Fratricide killing, prevalent in wild-type cells, is calcium and Pfr dependent, whereas the cell death of Pfr-deficient Th cells involves Fas and GrB but is calcium independent. This study identifies GrB as a new significant player in Th1/Th2 AICD and characterizes two mechanisms for the protective effect of VIP on Th2 survival, i.e., the down-regulation of GrB and FasL expression.

Animals↗

PubMed2006

Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis.

CD4(+)CD25(+) regulatory T cells (Treg) control the immune response to a variety of antigens, including self-antigens. Several models support the idea of the peripheral generation of CD4(+)CD25(+) Treg from CD4(+)CD25(-) T cells. Little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4(+)CD25(+) Treg. In this study we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg in vivo during the development of experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. The administration of VIP to EAE mice results in the expansion of the CD4(+)CD25(+), Foxp3-expressing T cells in the periphery and the nervous system, which inhibit encephalitogenic T cell activation. In addition to the increase in the number of CD4(+)CD25(+) Treg, VIP induces more efficient suppressors on a per cell basis. The VIP-generated CD4(+)CD25(+) Treg transfer suppression and significantly ameliorate the progression of the disease.

Adoptive Transfer↗

PubMed2006

Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation.

CD4+ CD25+ regulatory T cells (Treg) control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral generation of CD4+ CD25+ Treg from CD4+ CD25- T cells. However, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+ CD25+ Treg. We have found that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces functional Treg in vivo. The administration of VIP together with specific antigen to TCR-transgenic mice results in the expansion of the CD4+ CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. The VIP-generated CD4+ CD25+ Treg transfer suppression, inhibiting delayed-type hypersensitivity in the hosts, prevent graft-versus-host disease in irradiated host reconstituted with allogeneic bone marrow, and significantly ameliorate the clinical score in the collagen-induced arthritis model for rheumatoid arthritis and in the experimental autoimmune encephalomyelitis model for multiple sclerosis.

Animals↗

PubMed2006

Vasoactive intestinal polypeptide induces regulatory dendritic cells that prevent acute graft versus host disease and leukemia relapse after bone marrow transplantation.

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) with potent immunoregulatory properties by inducing the generation/activation of regulatory T cells (Tr) for the treatment of acute GVHD following allogeneic BMT has been recently established. Here we report the use of the known immunosuppressive neuropeptide, vasoactive intestinal polypeptide (VIP), as a new approach to inducing tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated with VIP impair allogeneic haplotype-specific responses of donor CD4+ T cells in transplanted mice by inducing the generation of Tr in the graft. Importantly, VIP-induced tolerogenic DCs did not abrogate the graft versus leukemia response, probably because they do not abrogate cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DC in future therapeutic regimens may facilitate the successful transplantation from mismatched donors, reducing the deleterious consequences of acute GVHD, extending the applicability of BMT.

Acute Disease↗

PubMed2006

Vasoactive intestinal peptide: the dendritic cell --> regulatory T cell axis.

Tolerogenic dendritic cells (tDCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tDCs. In this article, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), contribute to the development of bone marrow-derived tDCs. The VIP/PACAP-generated DCs are CD11clowCD45RBhigh, do not upregulate CD80, CD86, and CD40 following lipopolysaccharide (LPS) stimulation, and secrete high amounts of IL-10. The VIP/PACAP-generated DCs induce functional Treg in vitro and in vivo. VIP/DCs induce antigen-specific tolerance in vivo, suppress delayed-type hypersensitivity (DTH), and T cells from VIP/DC-inoculated mice transfer the suppression to naïve hosts. The effect of VIP/PACAP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly in anatomical sites that exhibit immune deviation or privilege.

Animals↗

PubMed2006

VIP prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease.

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system (CNS). Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a new possible strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), an MS-related rodent model. VIP suppressed EAE neuropathology by reducing CNS inflammation and by selective blocking encephalitogenic T-cell reactivity, emerging as an attractive candidate for the treatment of human MS.

Animals↗

PubMed2006

VIP protects Th2 cells by downregulating granzyme B expression.

Selective differentiation of Th1/Th2 effectors contributes to cell- or antibody-mediated immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. Here we investigate the mechanisms of VIP-induced Th2 survival. Microarray and protein data indicate that VIP prevents the upregulation of granzyme B (GrB) in Th2, but not Th1 effectors. This is the first report of GrB expression and of its involvement in activation-induced apoptosis of T helper cells. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors and alternative signaling pathways. This study identifies GrB as a new significant player in Th1/Th2 activation-induced cell death, and characterizes the mechanisms for the protective effect of VIP on Th2 survival.

Apoptosis↗

PubMed2006

Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses.

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.

Animals↗

PubMed2005

The neuropeptide vasoactive intestinal peptide generates tolerogenic dendritic cells.

Tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tolerogenic DCs. In this report, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), contribute to the development of bone marrow-derived tolerogenic DCs in vitro and in vivo. The VIP/PACAP-generated DCs are CD11c(low)CD45RB(high), do not up-regulate CD80, CD86, and CD40 following LPS stimulation, and secrete high amounts of IL-10. The induction of tolerogenic DCs is mediated through the VPAC1 receptor and protein kinase A, and correlates with the inhibition of IkappaB phosphorylation and of NF-kappaBp65 nuclear translocation. The VIP/PACAP-generated DCs induce functional Treg in vitro and in vivo. The VIP/DC-induced Treg resemble the previously described Tr1 in terms of phenotype and cytokine profile, suppress primarily Th1 responses including delayed-type hypersensitivity, and transfer suppression to naive hosts. The effect of VIP/PACAP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly in anatomical sites which exhibit immune deviation or privilege.

Animals↗

PubMed2005

Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo.

CD4+CD25+ regulatory T (Treg) cells control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral expansion of CD4+CD25+ Treg cells. Although hormones such as estrogen and alpha-melanocyte-stimulating hormone have been recently reported to expand the CD4+CD25+ Foxp3-expressing Treg cell compartment, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg cells. In this study, we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg cells in vivo. The administration of VIP together with specific antigen to T cell receptor (TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. In addition to the increase in the number of CD4+CD25+ Treg cells, VIP induces more efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+ Treg cells transfer suppression, inhibit delayed-type hypersensitivity in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow.

Animals↗

PubMed2005

Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders.

The induction of antigen-specific tolerance is critical for the prevention of autoimmunity and maintenance of immune tolerance. In addition to their classical role as sentinels of the immune response-inducing T cell reactivity, dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Tr). The possibility to generate tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Therefore, the characterization of the endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. In this study, we report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide, as a new approach to induce tolerogenic DCs with capacity to generate Tr cells, to restore tolerance in vivo, and to reduce the progression of rheumatoid arthritis and experimental autoimmune encephalomyelitis.

Animals↗

PubMed2004

Prostaglandin E2 promotes the survival of bone marrow-derived dendritic cells.

Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.

Animals↗

PubMed2004

A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2.

In response to pathogen-associated molecular patterns, dendritic cells initiate an innate immune response characterized by expression and release of proinflammatory cytokines and chemokines. The extent of the inflammatory response is limited by various endogenous factors, including lipid mediators such as prostaglandin E(2) (PGE(2)). We described previously the inhibitory effect of PGE(2) on the expression and release of the inflammatory chemokines CCL3 and CCL4 from activated dendritic cells. In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor. The direct link between CDP and CCL3/4 transcription was established in knock-down experiments using CDP small interference RNA.

Animals↗

PubMed2004

VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells.

The neuropeptides vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) are potent immunomodulatory agents, acting as general anti-inflammatory factors. VIP, produced and secreted by Th2 cells following antigen stimulation, participates in a Th2 autoregulatory loop, promoting Th2-type responses through several nonexcluding mechanisms. VIP and PACAP affect the differentiation of CD4+ T cells directly and indirectly through antigen-presenting cells and promote the proliferation and/or survival of the Th2 effectors. Th1 and Th2 effectors express different chemokine receptors that control migration in response to various chemokines. In this study, we investigated the effects of VIP/PACAP on the production of CXCL10 (a Th1 chemokine) and of CCL22 (a Th2 chemokine) by bone marrow-derived dendritic cells. We found that VIP and PACAP inhibit CXCL10, while promoting CCL22 production, and that the effects are mediated through the VPAC1 receptor and involve cAMP/PKA as intracellular messengers. The induction of CCL22 and the suppression of CXCL10 in VIP/PACAP-treated dendritic cells results in the preferential chemoattraction of Th2 effectors both in vivo and in vitro. This is in agreement with the general Th2 bias induced by the two neuropeptides and adds an important parameter to their immunomodulatory function. By promoting Th2 migration, and preventing or reducing Th1 infiltration in inflammatory foci and sites of antigen presentation, VIP and PACAP help in resolving acute inflammatory processes and contribute to the prevention of chronic inflammation.

Animals↗

PubMed2004

Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells.

Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.

Alprostadil↗