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

Dendritic cells (DC) are the main stimulators of primary T cell responses. Very little is known about DC in cord blood (CB), and whether they are involved in the low incidence and severity of GVHD following CB transplantation. Here, CBDC were identified as a HLA-DR+/lineage marker (lin; CD3, CD11b, CD14, CD16, CD19, CD34, CD56 and glycophorin A antigens) negative population, representing 0.3 +/- 0.1% (mean +/- s.d.; n = 15) of CB mononuclear cells. CBDC expressed the CD4, CD11a, CD18, CD45RA, CD50 and CD54 antigens but revealed no expression of the CD1a, CD11c, CD40, CD45R0, CD58, CD83, CD86 and CD102 antigens. Immunomagnetically enriched CBDC showed potent allostimulatory activity for CB T cells. Thus, CBDC are functionally competent and resemble in their immature/resting state CD11c- DC in peripheral blood.
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PMID:Functional competence of dendritic cells in human umbilical cord blood. 971 87

Despite complete matching of siblings for the HLA loci, after bone marrow transplantation (BMT), approximately 20% develop graft-versus-host disease (GVHD). This is presumably due to incompatibility of minor histocompatibility antigens (mHa). We investigated the polymorphisms of 14 adhesion molecules (CD2, CD28, CD31, CD34, CD36, CD42, CD44, CD48, CD49b, CD54, CD62L, CD86, CD102, and CD106) in Japanese subjects and their association with the occurrence of GVHD after allogeneic HLA identical BMT. Six molecules (CD2, CD31, CD42, CD49b, CD54, and CD62L), which were found to be polymorphic, were then examined in 118 HLA identical sibling donors and recipients who had undergone BMT. Association of the incompatibility of the polymorphic molecules with the presence or absence of GVHD was examined. In these six, we observed a significant correlation between acute GVHD and the compatibility of CD31 (codons 563/670) (Pcorrected = .018), and CD31 (codons 563/670) + CD62L (Pcorrected = .018) in patients with the HLA-B44-like superfamily. In patients with the HLA-A3-like superfamily, the compatibility of CD62L (Pcorrected = .03) and CD62L + CD49b (P = . 004, Pcorrected = .078) was associated with acute GVHD. Therefore, CD31, CD49b, and CD62L might be candidates for immunodominant mHa.
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PMID:Evidence that CD31, CD49b, and CD62L are immunodominant minor histocompatibility antigens in HLA identical sibling bone marrow transplants. 973 Oct 77

Intercellular adhesion molecule-1 (ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti-ICAM-1 and anti-LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r =.58, P <.05) between day 3 and 28. Treatment with anti-ICAM-1 (but not anti-LFA-1) decreased both the mean grades of portal inflammation (P =.003) and NSDC (P =.002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti-ICAM-1 and anti-LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti-ICAM-1, alone (P =.02). Anti-ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P <.01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti-ICAM-1 nor anti-LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC.
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PMID:Role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model. 1005 78

Graft versus host disease (GVHD) remains the major obstacle to the widespread application of allogeneic bone marrow transplantation (BMT) despite improvement in drug prophylaxis. T cells in the donor bone marrow recognize and react against host alloantigens and thereby initiate GVHD, but the precise mechanisms by which host tissues are damaged remain unclear. In the current study, we determined the cytokine secretion, cell population distribution, and cell surface markers expression by ELISA and flow cytometer, to understand further the pathophysiology of GVHD. Our results demonstrated that there was no significant change in the cell ratio of B-and T- lymphocytes, and helper/suppressor cells during GVHD development when compared to the condition before transplantation. Furthermore, the percentage of natural killer cells, the interleukin-2 receptor (IL-2R) or the HLA-DR antigen on both CD4 and CD8 positive cells presented no significant difference between pre-transplantation and during GVHD. The serum cytokine secretion of IL-1, TNF-alpha, IL-2, ICAM-1, endothelin, TGF-beta showed no difference before BMT and during GVHD. However, when patients in the developing of GVHD, there was significant difference in the serum levels of soluble IL-2R (slL-2R), epidermal growth factor (EGF), and platelet derived growth factor (PDGF). In addition, with patients who develop GVHD, the mixed lymphocyte reaction also presented a significant difference. This study indicated that some serum cytokines such as sIL-2R, growth factors, and the mixed lymphocyte reaction may be used as parameters for the early detection of the development of GVHD.
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PMID:Cell surface markers and circulating cytokines in graft versus host disease. 1007 84

Dendritic cells (DC) are the main stimulators of primary T-cell responses and, thus, probably play a role in the immune reactions after stem cell transplantation. Very little is known about DC in cord blood (CB) and about their potential involvement in the low incidence and severity of acute graft-versus-host disease after CB transplantation. Here, CBDC were identified as a HLA-DR+ cell population, lacking the CD3, CD11b, CD14, CD16, CD19, CD34, CD56, and glycophorin A lineage markers (lin). This lin-/HLA-DR+ population represented 0.3% +/- 0.1% (mean +/- SD; range, 0.1% to 0. 6%; n = 15) of CB mononuclear cells, and CB contained 5.4 +/- 3.2 x 10(3) CBDC/mL (1.8 to 13.0 x 10(3); n = 15). CBDC expressed CD4, CD11a, CD18, CD45RA, CD50, CD54, and CD123, but showed no expression of CD1a, CD11c, CD33, CD40, CD45R0, CD80, CD83, and CD86 and only limited expression of CD58, CD102, and CD116. Despite this immature phenotype, immunomagnetically lin--enriched CBDC were potent stimulators of allogeneic CB T cells. As few as 266 +/- 107 (193 to 530; n = 10) lin-/HLA-DR+ CBDC stimulated a significant response. However, CBDC failed to take up protein or peptide antigens. Thus, in CB there is a prevalence of a DC subpopulation, resembling the CD11c- DC identified in tonsils, the so-called plasmacytoid T cells, which may exert a function distinct from the CD11c+ DC subpopulation.
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PMID:Identification of cord blood dendritic cells as an immature CD11c- population. 1009 Sep 40

Umbilical cord blood (CB) transplantations are associated with a lower risk of severe graft-versus-host disease (GVHD) compared to BMT. GVHD is an immune reaction that involves interaction between cell surface molecules resulting in cell activation and release of many cytokines. Monocytes are known to be an important source of cell adhesion (CAM) and co-stimulatory molecules which play a crucial role in the efficient activation of T and B cells. We analyzed the phenotype of CB monocytes in the presence or absence of an inflammatory signal (rIFN-gamma) and compared them to adult blood (AB); the expression of HLA-DR and 17 different markers (CD11a, CD11b, CD11c, CD18, CD29, CD40, CD44, CD49a, CD49d, CD49e, CD49f, CD54, CD58, CD62L, CD80, CD86 and CD102) was measured by flow cytometry. Statistical analysis showed that, compared to AB, CB monocytes did not express CD11b, CD11c, CD49d and after stimulation with rIFNgamma, they lost the expression of CD58 and CD102, whereas CD80 and CD86 expression was induced. The analysis of fluorescence intensity (MFI) revealed that CB monocytes expressed some CAM (CD29, CD54, CD102) with a lower intensity than AB monocytes except CD44. In conclusion, absence and reduced expression of some markers argue for a different phenotypic profile of CB monocytes compared to AB monocytes, which might partly contribute to their impaired immune response and to the low incidence of GVHD observed after CB transplantations. However, CB monocytes expressed CD80 and CD86 co-stimulatory molecules, but this expression did not prove a normal co-stimulatory function.
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PMID:Expression of HLA-DR, CAM and co-stimulatory molecules on cord blood monocytes. 1116 18

Following allogeneic bone marrow transplantation (alloBMT), idiopathic pneumonia syndrome (IPS) and graft-versus-host disease (GVHD) caused by donor cell alloreactivity remain major obstacles to a successful outcome. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is involved in regulating lymphohematopoietic cell migration and facilitating T-cell responses. To determine whether ICAM-1 expression in the host would affect IPS or GVHD tissue injury responses, ICAM-1(-/-) mice were compared with ICAM-1(+/+) controls. ICAM-1(-/-) recipients did not exhibit the manifestations of IPS injury such as an increase in lung weights nor decreased lung function. The influx of T cells, macrophages, and neutrophils was dramatically dampened as was the production of the inflammatory cytokines interferon-gamma and tumor necrosis factor alpha and the chemokines monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and lymphotactin, normally upregulated in the lung during IPS. In contrast, systemic levels of these mediators were unaffected and GVHD-induced lesions in the liver and colon did not differ in severity regardless of ICAM-1 expression. GVHD-mediated mortality was accelerated in ICAM-1(-/-) recipients at doses of allogeneic spleen cells that are otherwise not uniformally lethal. These data implicate ICAM-1 as playing a critical role in the generation of IPS; therefore, ICAM-1 may be a discerning element, segregating IPS from GVHD injury post-alloBMT.
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PMID:Intercellular adhesion molecule-I (ICAM-I, CD54) deficiency segregates the unique pathophysiological requirements for generating idiopathic pneumonia syndrome (IPS) versus graft-versus-host disease following allogeneic murine bone marrow transplantation. 1152 86

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
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PMID:Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development. 1158 47

We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLA-identical BMT was performed for patients with acute (n = 39) or chronic leukemia (n = 68). Genotyping was performed in 107 D/R DNA pairs for gene polymorphisms of cytokines (tumor necrosis factor-alpha [TNF-alpha] and TNF-beta, interleukin-1 receptor antagonist [IL-1Ra], IL-6, and IL-10), adhesion molecules (CD31 and CD54), Fcgammareceptors (FcgammaRIIa, IIIa, IIIb), mannose-binding lectin (MBL), and myeloperoxidase (MPO). First infection (overall) and first episodes of bacterial, viral, or invasive fungal infection were studied retrospectively for 180 days after BMT. Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the FcgammaRIIa R-131 genotype (hazard ratio [HR] = 1.92; P =.04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR = 2.16; P =.03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were FcgammaRIIIb HNA-1a/HNA-1b (HR = 1.77; P =.002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR = 2.17; P =.017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P =.03 and P =.03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were FcgammaRIIIb HNA-1a/HNA-1a or HNA-1b/HNA-1b (HR = 2.57; P =.05) and donor MPO genotype was AA (HR = 5.14; P =.004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients.
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PMID:Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. 1239 99

The kinetics of gene expression associated with the development of cutaneous graft-versus-host disease (GVHD) were examined in a mouse model of MHC-matched allogeneic hematopoietic stem cell transplantation. Ear skin was obtained from recipient mice with or without GVHD between 7 and 40 days after transplantation for histopathological analysis and gene expression profiling. Gene expression patterns were consistent with early infiltration and activation of CD8(+) T and mast cells, followed by CD4(+) T, natural killer, and myeloid cells. The sequential infiltration and activation of effector cells correlated with the histopathological development of cutaneous GVHD and was accompanied by up-regulated expression of many chemokines and their receptors (CXCL-1, -2, -9, and -10; CCL-2, -5, -6, -7, -8, -9, -11, and -19; CCR-1 and CCR-5), adhesion molecules (ICAM-1, CD18, Ly69, PSGL-1, VCAM-1), molecules involved in antigen processing and presentation (TAP1 and TAP2, MHC class I and II, CD80), regulators of apoptosis (granzyme B, caspase 7, Bak1, Bax, and BclII), interferon-inducible genes (STAT1, IRF-1, IIGP, GTPI, IGTP, Ifi202A), stimulators of fibroblast proliferation and matrix synthesis (interleukin-1beta, transforming growth factor-beta1), and markers of keratinocyte proliferation (keratins 5 and 6), and differentiation (small proline-rich proteins 2E and 1B). Many acute-phase proteins were up-regulated early in murine cutaneous GVHD including serum amyloid A2 (SAA2), SAA3, serpins a3g and a3n, secretory leukocyte protease inhibitor, and metallothioneins 1 and 2. The kinetics of gene expression were consistent with the evolution of cutaneous pathology as well as with current models of disease progression during cutaneous GVHD.
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PMID:Kinetics of gene expression in murine cutaneous graft-versus-host disease. 1516 52


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