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)

Injection of parental lymphocytes into an unirradiated adult F1 host results in an acute GVH reaction characterized by immune deficiency, attack on host lymphohematopoietic tissues, and repopulation with donor-derived cells. All of these events result from the initial activation of donor lymphocytes by host alloantigens. Interaction of pairs of host and donor costimulatory molecules, in particular CD28/CTLA4 and B7-1/B7-2, play a crucial role in this initial activation of donor T cells. We demonstrate here that in vivo treatment of the host with high doses of CTLA4-Ig solely during the initial period of donor alloactivation can completely abort the subsequent development of GVH reaction. Although donor T cells are retained, CTLA4-Ig treatment reduces the initial endogenous cytokine production and arrests the subsequent expansion of donor T cells, the differentiation of anti-host effectors, and the development of severe immune deficiency. This result is consistent with the establishment of host-specific tolerance in the donor population, while maintaining host immune competence.
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PMID:Acute graft-versus-host reaction can be aborted by blockade of costimulatory molecules. 763 32

In addition to presentation of antigen, T cells require additional or 'costimulatory' signals from antigen-presenting cells. Failure to receive costimulation following antigen presentation renders T cells anergic, and these cells are functionally incapable of proliferating or secreting cytokines in response to subsequent rechallenge. Recent evidence has demonstrated that a critical costimulatory signal is delivered by members of the B7 family. B7-1 (CD80) and B7-2 (CD86) provide costimulation through CD28, their ligand on the T cell. Dysregulation of expression of B7 may be implicated in the pathogenesis of autoimmune disease. In contrast, lack of expression of B7 on tumor cells may explain in part the lack of immune response against the majority of tumors. It may now be possible to exploit this pathway to induce immunological response against tumors. Blockade of this pathway will likely have significant impact on transplantation biology, to induce T-cell anergy and prevent graft rejection and graft-versus-host disease.
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PMID:B7-mediated costimulation and the immune response. 881 43

Bile duct cells (BDCs), especially intrahepatic cholangiocytes, are primary targets of immune-related injury in such pathologic processes as liver graft rejection, liver graft-versus-host disease, and primary sclerosing cholangitis. Cholestasis and progressive loss of intrahepatic BDCs indicate chronicity in these diseases. The present investigation characterizes the acquisition of immune markers of intrahepatic BDCs isolated from mice after bile duct ligation. Purified BDCs from cholestatic C57BL/6 (H-2b) mice express not only the major histocompatibility complex (MHC) class I and class II antigens but also the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The expression of the MHC class II molecules on BDCs before and after interferon (IFN)-gamma exposure is also demonstrated by immunohistochemistry on the cultured cells. Cytotoxicity assays indicate the vulnerability of these cells as targets for immunologic injuries. Effector cells generated from B10.BR splenocytes (H-2k) against C57BL/6 splenocytes (H-2b) show comparable killing of BDCs and EL4 cells, the latter being a lymphoma line that was established from the C57BL/6N (H-2b) mouse. An immortalized mouse BDC line (IBDC) is included in this study to validate some of the findings from BDCs isolated from bile duct-ligated mice. We suggest that cholestatic BDCs express surface antigens different from those of normal epithelial cells that result in increased susceptibility to damage by immune mechanisms.
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PMID:Phenotypical and functional characterization of intrahepatic bile duct cells from common duct ligated mice. 896 Jun 34

T lymphocyte activity is enhanced by costimulatory signals mediated through CD28 binding to B7-1/B7-2 on antigen-presenting cells. Several recent studies have shown that graft-versus-host disease (GVHD) can be inhibited by in vivo treatment with CTLA4Ig, which blocks CD28-B7 interactions. These findings prompted us to investigate the role of CD28 in acute GVHD, using gene-targeted mice. We performed the experiments in the context of strong allogeneic MHC stimulation (H2(b) anti-H2(d)) and weak stimulation (H2(d) anti-H2(b)). In both directions, efficient in vitro T-cell cytotoxicity and acute lethal GVHD were induced by CD28-deficient lymphocytes, which was only partially delayed when compared with wild-type mice. We conclude that lethal GVHD can develop without costimulation via CD28.
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PMID:Acute graft-versus-host disease without costimulation via CD28. 911 66

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) is a molecule expressed on in vitro activated T cells. CTLA-4 shares important sequence homology with CD28 and binds to the same ligands, CD80 (B7-1) and CD86 (B7-2). CTLA-4 probably functions as a negative regulator of T lymphocyte activation in the mouse, although this remains to be proven for human T lymphocytes. We have developed new monoclonal antibodies against human CTLA-4 and have investigated the in situ expression of CTLA-4 in a wide variety of normal and pathological human tissues expressing CD80 and CD86. As revealed in this study, CTLA-4 is expressed on thymocytes in thymic medulla, on a subset of CD4+ T lymphocytes in germinal centers of follicular hyperplasia, on T cells, mainly CD8+, infiltrating skin affected by graft-versus-host disease, and on T cells, mainly CD4+, infiltrating Hodgkin's disease lesions. In immunoelectron microscopy, CTLA-4 was found on the plasma membrane as well as in the hyaloplasm and cytoplasmic vesicles, in agreement with its pattern of expression on in vitro activated T cells. Interestingly, no or at most scarce expression of CTLA-4 was found in granulomatous lymph nodes, T-cell-mediated inflammatory diseases, or non-Hodgkin's lymphomas, regardless of their expression of CD80 or CD86. Thus, expression of CTLA-4 appears to be induced in selective pathological conditions in vivo. The pathways leading to selective induction of CTLA-4 and its role in the pathophysiology of these conditions need to be further investigated.
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PMID:Human CTLA-4 is expressed in situ on T lymphocytes in germinal centers, in cutaneous graft-versus-host disease, and in Hodgkin's disease. 954 57

Nonsuppurative destructive cholangitis (NSDC), a process of T-cell-mediated destruction of biliary epithelia observed in primary biliary cirrhosis (PBC), graft-versus-host disease (GVHD), and hepatic allograft rejection (HAR), also occurs in the B10. D2-->BALB/c model of GVHD. To advance studies of immunopathogenesis in this murine model, we immortalized 4 BALB/c intrahepatic biliary epithelial cell (BEC) lines as a reliable source of target cells. Freshly isolated BEC, as well as each cell line, expressed cytokeratin-19 (CK-19), epithelial cell adhesion molecule (EPCAM) and cystic fibrosis transmembrane conductance regulator (CFTR). None expressed albumin. Immortalized cells also expressed SV40 large T antigen. Class I major histocompatibility complex (MHC) was expressed by >97% of immortalized cells, while class II MHC and intercellular adhesion molecule-1 (ICAM-1) expression ranged from 0% to 13% and 14% to 74%, respectively. Interferon gamma (IFN-gamma) induced aberrant class II MHC expression and increased expression of ICAM-1. Variable proportions of immortalized cells expressed B7-1/B7-2 molecules and FAS. IFN-gamma significantly reduced B7-1 expression in some lines and significantly increased B7-2 expression in others. Allografts of freshly isolated and immortalized BEC injected into subscapular fat pads spontaneously formed duct-like structures. Inflammation was absent in BALB/c recipients. In contrast, inflammatory lesions in B10.D2 recipients were reminiscent of NSDC. Our results indicate that BALB/c-immortalized intrahepatic biliary cells: 1) retain the phenotype of mouse BEC; 2) can be induced to express aberrant class II MHC and increased ICAM-1; 3) express costimulatory B7-1/B7-2 molecules and FAS; and 4) spontaneously form duct-like structures after in vivo injection that are immunogenic in B10.D2 mice. These cell lines should facilitate future studies of the immunopathogenesis of NSDC in the B10. D2-->BALB/c murine model.
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PMID:Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity. 1042 41

A c-myc retrovirus-transformed myeloid leukemia line, MMB3.19, of C57BL/6 (B6) origin, was developed to investigate graft-versus-leukemia (GVL) activity in murine bone marrow transplantation (BMT) models. It was previously determined that both naive and leukemia-presensitized CD4+-enriched T cells are capable of mediating GVL activity to MMB3.19 challenge in both syngeneic (B6) and allogeneic (C3H.SW-->B6) strain combinations, with the latter coinciding with minimal graft-versus-host disease. In the present study, MMB3.19 and 2 other similarly derived, yet phenotypically diverse, B6 myeloid leukemia lines (MMB1.10 and MMB2.18) were investigated for potential shared tumor antigens in the syngeneic GVL model. Morphologically, all 3 tumor lines are blastic with high cytoplasmic:nuclear ratios, but MMB2.18 displays dendritic processes, whereas MMB1.10 and MMB3.19 have a more rounded appearance. Flow cytometric analysis of the 3 lines revealed constitutive surface molecule expression of Mac-1, Mac-2, F4/80, LFA-1, B7-1, B7-2, H2Kb, H2Db, and macrophage scavenger receptor, consistent with macrophage/monocyte lineages. Furthermore, each of the lines expresses H2I-Ab, but to varying degrees, with MMB2.18 cells having the lowest percentage (31.6%). In vitro 51Cr release assays using MMB3.19-primed T-cell effectors demonstrated equivalent specific lysis of all 3 leukemia-line target cells. In addition, enzyme-linked immunospot analysis of MMB3.19-primed CD4+ T cells revealed significantly increased frequencies of tumor-stimulated interleukin (IL)-2-, IL-4-, and interferon-gamma-secreting cells when restimulated with each of the 3 leukemia lines. Furthermore, when MMB3.19-primed CD4+ T cells were administered in a BMT setting, a protective GVL effect was seen in those mice challenged with MMB1.10, MMB2.18, or MMB3.19. Therefore, in vitro and in vivo experiments indicate that the 3 distinct myeloid leukemia lines share 1 or more common major histocompatibility complex class II-restricted tumor antigens that can elicit a cross-protective in vivo T-cell GVL response.
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PMID:Cross-protective murine graft-versus-leukemia responses to phenotypically distinct myeloid leukemia lines. 1107 Dec 59

Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors.
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PMID:Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. 1127 1

To detect effects of B7 co-stimulation on cytokines, especially on IL-2 mRNA and transcription factors NF-kappa B and AP-1, antiB7-1 McAb, antiB7-2 McAb and C TLA-4 Ig were added into mixture lymphocyte reaction (MLR) system to block B7/C D28 signal transduction, IL-2 mRNA and IL-4 mRNA were determined by using competitive PCR and IFN-gamma mRNA by using semi-quantitative PCR. MHC class II molecules and B7 transfectants were used to stimulate CD28(+) T cell, effects of B7 on NF-kappa B and AP-1 were detected by DNA-protein binding assay. The results showed that IL-2, IL-4 and IFN-gamma mRNA were significantly lower when blockade of B7-2 in MLR than blockade of B7-1. Synergistic effects could be seen with combination of two or three antibodies. One to six hours after MLR, tDR7 alone induced NF-kappa B binding activity; cotransfecting B7 no significantly difference at early time point. After 6 hours, induction of tDR7 was decreased whereas B7 prolonged the induction of NF-kappa B till 72 hours. tDR7 alone also upregulated AP-1 binding activity, on the contrary to NF-kappa B, co-transfecting B7-1 and B7-2 decreased AP-1 binding activity within 24 hours. But during 48 - 72 hours, B7 also prolonged the AP-1 binding activity. It is concluded that after MLR, B 7 increased IL-2 secretion by decreasing the degradation of IL-2 mRNA and upregulating IL-2 transcription factors. B7 also induced several kinds of cytokines secretion. Effects of B7-1 and B7-2 had no significant difference on transcription factors. It is suggested that the different functions between B7-1 and B7-2 maybe related to the difference of cell expression and kinetics. To study the molecular mechanism of B7 mediated T cell immune tolerance can help us to design a better clinic schema to prevent transplantation rejection and GVHD.
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PMID:[The identical effects of B7-1 and B7-2 on regulation of human IL-2 gene transcription factors NF-kappa B and AP-1]. 1251 11

Graft-versus-host disease (GVHD) is a potentially fatal complication after allogeneic bone marrow transplantation. However, few data exist thus far on the molecular signals governing leukocyte trafficking during the disease. We therefore investigated the sequential pattern of distinct adhesion, costimulatory, and apoptosis-related molecules in GVHD organs (ileum, colon, skin, and liver) after transplantation across minor histocompatibility barriers (B10.D2 --> BALB/c, both H-2d). To distinguish changes induced by the conditioning regimen from effects achieved by allogeneic cell transfer, syngeneic transplant recipients (BALB/c --> BALB/c) and irradiated nontransplanted mice were added as controls. Irradiation upregulated the expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-l, and B7-2 in ileum, as well as VCAM-1 and B7-2 in colon, on day 3 in all animals. Whereas in syngeneic mice these effects were reversed from day 9 on, allogeneic recipients showed further upregulation of VCAM-1, ICAM-1, B7-1, and B7-2 in these organs on day 22, when GVHD became clinically evident. Infiltration of CD4+ and CD8+ donor T cells was noted on day 9 in skin and liver and on day 22 in ileum and colon. Surprisingly, the expression of several other adhesion molecules, such as ICAM-2, platelet-endothelial cell adhesion molecule 1, E-selectin, and mucosal addressin cell adhesion molecule 1, did not change. Proapoptotic and antiapoptotic markers were balanced in GVHD organs with the exception of spleen, in which a preferential expression of the proapoptotic Bax could be noted. Our results indicate that irradiation-induced upregulation of VCAM-1, ICAM-1, and B7-2 provides early costimulatory signals to incoming donor T cells in the intestine, followed by a cascade of proinflammatory signals in other organs once the alloresponse is established.
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PMID:Sequential expression of adhesion and costimulatory molecules in graft-versus-host disease target organs after murine bone marrow transplantation across minor histocompatibility antigen barriers. 1584 91


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