Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral blood stem cells (PBSC) obtained from granulocyte-colony stimulating factor (G-CSF)-mobilized donors are increasingly used for allogeneic transplantation. Despite a 10-fold higher dose of transplanted T cells, acute graft-versus-host disease (GVHD) does not develop in higher proportion in recipients of PBSC than in recipients of marrow. T cells from G-CSF-treated experimental animals preferentially produce IL-4 and IL-10, cytokines characteristic of Th2 responses, which are associated with diminished GVHD-inducing ability. We hypothesized that G-CSF-mobilized PBSC contain antigen-presenting cells, which prime T-lymphocytes to produce Th2 cytokines. Two distinct lineages of dendritic cells (DC) have been described in humans, DC1 and DC2, according to their ability to induce naive T-cell differentiation to Th1 and Th2 effector cells, respectively. We have used multicolor microfluorometry to enumerate DC1 and DC2 in the peripheral blood of normal donors. G-CSF treatment with 10 to 16 microg/kg per day for 5 days increased peripheral blood DC2 counts from a median of 4.9 x 10(6)/L to 24.8 x 10(6)/L (P =.0009), whereas DC1 counts did not change. Purified DC1, from either untreated or G-CSF treated donors, induced the proliferation of allogeneic naive T cells, but fresh DC2 were poor stimulators. Tumor necrosis factor-alpha (TNF-alpha)-activated DC1 induced allogeneic naive T cells to produce IFN-gamma, which is typical of Th1 responses, whereas TNF-alpha-activated DC2 induced allogeneic naive T cells to produce IL-4 and IL-10, which are typical of Th2 responses. PBSC transplants contained higher doses of DC2 than marrow transplants (median, 2.4 x 10(6)/kg versus 0.5 x 10(6)/kg) (P =.006), whereas the dose of DC1 was comparable. Thus, it is conceivable that transplantation of G-CSF-stimulated PBSC does not result in overwhelming acute GVHD because the graft contains predominantly Th2-inducing DC. Adoptive transfer of purified DC2 may be exploited to induce immune deviation after transplantation of hematopoietic stem cells or organ allografts. (Blood. 2000;95:2484-2490)
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PMID:Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. 1119 28

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1-mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4-dependent manner. Thus, it is important to understand how the development of IL-4- versus interferon (IFN)-gamma-producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500-70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-gamma, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4(+)IFN-gamma(-) NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4(-)IFN-gamma(+) NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4(+)IFN-gamma(-) NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-gamma.
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PMID:Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells. 1136 93

Graft-versus-host disease (GVHD), a major complication after allogeneic transplantation, can be abrogated by the Campath (anti-CD52) monoclonal antibody. The induction of acute GVHD requires host antigens to be presented to donor T cells by antigen-presenting cells (APCs). Recent evidence has suggested that only host APCs can interact with donor T cells in the induction of GVHD. Because CD52 has been reported to be expressed on DCs, we reasoned that pretransplant Campath-1G might have a direct effect on circulating DCs in addition to any effects on donor T cells. Using direct immunostaining, we demonstrated expression of CD52 on DCs and that Campath-1G killed purified DCs in vitro. In vivo Campath also depleted DCs. Twenty-four hours after the first dose of Campath-1G, circulating DCs were reduced by a mean of 79% (range, 44%-96%). By day 0 after 5 doses of Campath-1G and chemoradiotherapy conditioning, DCs became undetectable in 7 of 9 cases, whereas in 6 of 7 patients receiving conditioning therapy without Campath-1G, host DCs were still detectable. The reconstitution of circulating DCs after transplantation was not affected by Campath-1G and in both groups DC1 (CD11c(+)) recovered more rapidly than DC2 (CD11c(-)). Analysis of chimerism confirmed that the DCs recovering after transplantation in patients receiving Campath-1G were of donor origin. We conclude that in vivo Campath-1G causes a rapid depletion of host circulating DCs and that this may, in part, explain the low incidence of acute GVHD. The reconstitution of donor DCs was not delayed, which may be important in preserving immune reconstitution.
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PMID:Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution. 1189 97

Despite significant advances in stem cell manipulation and post-transplant immunosuppression, chronic graft-versus-host disease (cGVHD) remains a cause of major long-term morbidity in survivors of allogeneic stem cell transplantation. Extracorporeal photopheresis (ECP) is a novel therapeutic intervention which has demonstrated efficacy in patients with refractory acute and chronic GVHD. Clinical responses have been reported in skin and visceral GVHD. While the long-term immunomodulatory effects of ECP in cGVHD are unknown, recent studies of patients undergoing a 6- to 12-month course of ECP treatment demonstrated an attenuation of Th1-mediated cytokine secretion by activated T-helper cells, a shift in the DC1/DC2 ratio favoring plasmacytoid rather than monocytoid dendritic cell profiles, and a decrease in antigen responsiveness by dendritic cells. The implications of these immunomodulatory effects of ECP on pathogenesis and clinical outcome remains a fertile area for future research.
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PMID:Extracorporeal photopheresis in chronic graft-versus-host disease. 1204 Apr 67

Extracorporeal photochemotherapy (ECP) has been shown to be an effective therapy for patients with acute and chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation, but its biologic mechanism is not understood. We reported that clinical response to ECP was associated not only with normalization of skewed CD4/CD8 ratios but also with an increase in CD3(-)/CD56(+) natural killer cells and a decrease in the number of CD80(+) and CD123(+) circulating dendritic cells (DCs). To further elucidate the effects of ECP on activated lymphocyte subpopulations and the interaction between effector lymphocytes and antigen-presenting DCs, we isolated and characterized DC populations from patients with chronic GVHD undergoing ECP therapy. Antigen-presenting activity of DCs was measured as proliferation of antigen-stimulated autologous and allogeneic T cells by mixed-lymphocyte reaction (MLR). In MLR assays the proliferation of T cells was decreased in all 10 patients by a mean of 84% (range, 75%-95%; P < or =.002) after a 2-day cycle of ECP and longitudinally over the 12-month course of therapy. Immunophenotypic analysis of DC populations revealed a preponderance of DC1 monocytic dendritic cells in all patients before the initiation of ECP. Nine of 10 patients demonstrated a shift from DC1 to DC2 and as a concordant shift from a predominantly Th1 (interleukin-2 [IL-2], interferon-gamma) to Th2 (IL-4, IL-10) cytokine profile after ECP, and 8 of 10 had a clinical response to ECP. Our results suggest that ECP alters alloreactivity by affecting allo-targeted effector T cells and antigen-presenting DCs.
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PMID:Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. 1213 May 6

Suppression by T-regulatory (Tr) cells is essential for the induction of T-cell tolerance and the prevention of autoimmune diseases, organ rejection, and graft-versus-host disease. Increasing attention has been devoted to understand the role of dendritic cells (DC) in the control of Tr-cell differentiation. Here we review the recent evidence that cluster designation (CD)40-ligand activated plasmacytoid-derived DCs (DC2) have the ability to induce primary Tr-cell differentiation. We propose that in addition to the regulatory functions of immature myeloid DC, Tr-cell induction by DC2 represents a nonredundant mechanism for the safeguard of peripheral T-cell tolerance. DC2 can be used as tool to drive potent antigen specific Tr-cell differentiation and expansion in vitro and in vivo.
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PMID:Human plasmacytoid-derived dendritic cells and the induction of T-regulatory cells. 1248 Feb 58

Allogeneic G-CSF-mobilized blood cell transplantation (BCT), an alternative to allogeneic bone marrow transplantation (BMT), is associated with enhanced engraftment and accelerated hematopoietic recovery. In addition, immune reconstitution and overall alloreactivity after BCT versus BMT differ significantly. Indeed, despite an increased number of donor T cells infused, the incidence of acute graft-versus-host disease (GvHD) after BCT appears to remain identical or lesser than after BMT. On the other hand, a higher risk of chronic GvHD has been reported after BCT. In a SFGM phase III trial, 101 patients with early leukemia and an HLA-matched sibling donor randomly received a BCT or BMT. BCT was associated with a higher number of infused CD34+ cells, accelerated platelet and neutrophil reconstitution, fewer platelet transfusions and similar acute GvHD incidence. However, chronic GvHD occurred more frequently after BCT. With a median follow-up of 20 months, relapse, survival and leukemia-free survival were not different. In the course of this study, immune parameters related to the graft as well as to early reconstitution were prospectively examined. T cells subsets, B cells, NK cells and monocytes numbers were significantly higher in BC grafts (versus BM). T cells in BC grafts were less activated than in BM grafts. Frequency of IFN-gamma, IL-2- and TNF-alpha-secreting cells and single-cell IFN-gamma production potential was reduced in BC graft. One month after BCT, blood T-cell counts were 3-fold higher than after BMT. Moreover, post-BCT T cells were less activated and counts correlated with the number of T cells infused with the graft, which was not the case after BMT. Several acute hemolysis episodes, resulting from anti-A and/or -B donor-derived Ab directed at Ag present on recipient red blood cells (minor ABO mismatch), have been described after BCT. Recipients indeed exhibited significantly increased anti-A and/or -B Ab titers after BCT, particularly in the setting of a "minor" ABO mismatch. Furthermore, the frequency of anti-HLA Ab early after BCT was significantly increased (despite the reduction in platelet transfusion requirements). The higher number of activated B cells and/or CD4 T cells and monocytes in a BCT graft and/or the higher number of circulating CD4 T- and B-cells after BCT could be associated with the enhanced alloAb production. G-CSF-induced TH2 cytokine profile of the T cells present in the graft could also be contributive. Recent studies have determined that BC grafts contained a higher number of type 2 dendritic cells (DC2), themselves associated with high frequencies of TH2 CD4+ cells. Since chronic GvHD is associated with the occurrence of Ab-mediated auto-immune-like syndromes, it is tempting to speculate that a higher incidence of chronic GvHD may result from these findings. In conclusion, BCT results in clinically relevant distinct hematopoietic and immune reconstitution patterns.
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PMID:Blood versus marrow hematopoietic allogeneic graft. 1287 95

Extracorporeal photochemotherapy (ECP) has been shown to be effective in variety of pathologic diseases such as Sezary syndrome, autoimmune diseases, organ graft rejection and graft versus host disease. However, its mechanism of action has remained elusive. Understanding of its mechanisms may be useful to identify the best indications, treatment regimes and to optimize the ECP technique. The first step of the ECP procedure is collection of peripheral mononuclear cells. In this step, several cell environment changes occur. These conditions have been suggested to increase monocyte activation and possibly drive dendritic cell differentiation. The second step of ECP is the cell radiation by UVA in presence of 8-MOP which is presumed to induce cell membrane damage, DNA crosslinking and binding to a variety of cytosolic proteins leading to apoptosis, modification of membrane antigenicity and antigen presenting cell activation. The third step of ECP is the reinfusion of the treated cells to the patient. While it is unclear what exactly occurs in vivo, it is thought that DCs play a critical role by inducing an immunological response against pathogenic cells. The immature DC, activated by ECP, phagocytizes and internalizes the apoptotic cells; processes the antigens and increases the synthesis of class I and II Major Histocompatibility Complex (MHC) molecules. The peptides associated with class II MHC are presented to the CD4+ T helper cells. The final maturation of DC is completed in vivo with the help of these activated T helper cells using a variety of mechanisms including CD40 ligation. Finally, the mature DCs fully loaded with pathogenic T cell peptides migrate to secondary lymphoid organs stimulate the naive CD8+ T cells and induce a cytotoxic response (Th1 immune response) directed against pathogenic clones (tumoral cells of Sezary syndrome). Clinical and haematological improvement after ECP in Sezary syndrome is associated with a shift in Th1/Th2 balance and the increase of Th1 cytokines and IL12. ECP can also down regulate the allo or autoimmune response and induces tolerance by regulatory T cells. The clinical response to ECP in patients with chronic GvHD is associated with increase in NK cells and a shift from DC1 to DC2 and a shift from predominantly Th1 to Th2 immune response. Recruitment and involvement of other immune cells in the mechanism of ECP have been suggested and merit more studies. This immunostimulatory capacity of ECP is the most probable hypothesis of its mechanism but further investigations are necessary to determine the precise players important for this activity.
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PMID:Mechanisms of action of extracorporeal photochemotherapy. 1287 96

Dendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (< 4.97 cells/microL) were found to have significantly worse survival (P =.002), increased incidence of relapse (P =.002), higher incidence of aGVHD onset (P =.0005), and a composite end point of relapse or death (P =.0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P =.02), time to relapse (HR, 11.6; P =.001), and aGVHD (HR, 3.3; P =.04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT.
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PMID:Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. 1496 4

Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [T(H)1] and T(H)2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor alpha (TNF-alpha) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused T(H)1 cells to decrease interferon gamma (IFN-gamma) and caused the T(H)2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (T(Regs)) present; and hMSCs decreased secretion of IFN-gamma from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE(2)) in co-cultures, and inhibitors of PGE(2) production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation.
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PMID:Human mesenchymal stem cells modulate allogeneic immune cell responses. 1549 28


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