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)

The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.
 ...
PMID:Effector mechanisms of nonsuppurative destructive cholangitis in graft-versus-host disease and allograft rejection. 1614 44

Aims-To determine which inflammatory and immune pathways are implicated in the development of chronic graft versus host disease (GvHD) and whether differences between these pathways are responsible for the different presentations of chronic GvHD.Methods-Biopsy specimens of diseased and normal skin were obtained from patients presenting with lichen planus-like and sclerodermatous type chronic GvHD. Expression of epidermal cytokines, adhesion molecules and lymphoid surface markers was analysed by means of immunohistochemistry. Apoptosis was detected using the in situ nick endlabelling method.Results-In both GvHD lesion types, CD8+ cells predominated in the epidermis, whereas CD4+ cells were the most prevalentin the dermis. Apoptotickeratinocytes were found in diseased skin only and Fas antibodies labelled a considerable number of keratinocytes. The epidermis in both types of lesions expressed interleukin (IL) 1alpha, tumour necrosis factor (TNF) alpha and intercellular adhesion molecule (ICAM)-1, but dermal vascular cell adhesion molecule (VCAM)-1 expression was restricted to specimens of lichen planus-like GvHD. IL1alpha and E-selectin were expressed in normal looking skin of 55% and 80%, respectively, of patients with lichen planus-like GvHD.Conclusion-The similarity between expression of epidermal cytokines and adhesion molecules (with the exception of VCAM-1) and lymphocyte phenotype in lichen planus-like and sclerodermatous GvHD strongly suggests that the latter occurs as a consequence of the healing process. VCAM-1 distinguishes between lichen planus-like and sclerodermatous lesions. IL1alpha and E-selectin are potential early markers of chronic GvHD.
 ...
PMID:Lymphocytes, cytokines and adhesion molecules in chronic graft versus host disease. 1669 80

Induction of apoptosis and changes to cytokine secretion patterns have been implicated in the mechanism of action of extracorporeal photopheresis (ECP). Lymphocyte apoptosis is initially detected in significant numbers prior to re-infusion and by 48 h post-ECP the majority of treated lymphocytes are apoptotic. The early apoptosis involves changes to mitochondrial function, reversal of the Bcl-2/Bax ratio and externalisation of phosphatidylserine. Apoptotic lymphocytes, observed from 20 h post-ECP, are associated with enhanced levels of CD95 and Fas-ligand. For cutaneous T cell lymphoma (CTCL), processing of the apoptotic lymphocytes, by suitable antigen presenting cells (APCs), is suggested to induce a clonal cytotoxic response which targets the malignant T cell population. Increased levels of TNFalpha and IFNgamma, observed post-ECP in monocytes and lymphocytes, respectively, are thought to further contribute to the proposed anti-tumour reaction seen in CTCL. However, down-regulation of pro-inflammatory cytokines and enhanced anti-inflammatory responses have been reported following ECP treatment. These immune responses may contribute to the tempering of the inflammatory conditions, such as graft versus host disease, which respond to ECP. Furthermore, untreated monocytes exposed to ECP-treated lymphocytes have also demonstrated a shift in monocyte cytokine-secretory pattern, toward one associated with immune tolerance. Recently, a mechanism of ECP-induced immune tolerance has been linked to the stimulation of the anti-inflammatory cytokines IL10 and TGFbeta by T regulatory cells, following the infusion of ECP-treated CD11c(+) APCs. Ultimately, the multifaceted responses, induced by ECP, may explain the diversity of clinical conditions that benefit.
 ...
PMID:Extracorporeal photopheresis: a focus on apoptosis and cytokines. 1679 26

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4(+) T-cell cytokines and increased apoptosis of donor CD4(+) T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4(+) T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.
 ...
PMID:Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease. 1736 37

The induction of transplantation tolerance and the improvement of immune reconstitution after allogeneic bone marrow transplantation are the main research fields in the clinic organ transplantation and transplantation immunology. Over the past 5 years serial studies have been performed in our lab to induce robust transplantation tolerance by using combined strategies and improve the immune reconstitution of mice following allogeneic bone marrow transplantation by using gene-engineered bone marrow stromal cells. The results are encouraging. (1) The long-term survival of allografts was received by blockade of both CD28/B7 and CD40/CD40L or CD28/B7 and OX40/OX40L costimulation signals. In the case of blockade of both CD28/B7 and OX40/OX40L, the islet allograft survival was over 150 days compared to the control 14 days. (2) The CTLA4Ig-FasL fusion molecule expressed by adenoviral vector containing CTLA4Ig-FasL gene can prevent the autoimmune diabetes of mice and significantly prolong the survival time of cardiac allografts in rats, indicating that Fas-FasL-mediated apoptosis is able to enhance CTLA4Ig-induced transplantation tolerance. (3) In the time-window of peripheral tolerance induced by various methods, the systemic infusion of donor bone marrow cells and spleen cells obtained stable allogeneic mixed chimerism and robust transplantation tolerance. In the case of CTLA4Ig-FasL treatment combined with donor bone marrow cells more than 20% donor-origin blood cells chimerism, and more than 200 days prolonged skin allograft survival were obtained or received. (4) The murine bone marrow stromal cell line QXMSC1 transfected with IL-6 gene or IL-2+IL-3 genes significantly improved the immune reconstitution of mice following allogeneic bone marrow transplantation. Furthermore, It was observed that the mesenchymal stem cells transfected with IL-7 gene suppressed 90% of GVHD and expressed antileukemic effect, while accelerating immune reconstitution in mice following allogeneic bone marrow transplantation, which might be valuable in the clinic setting.
 ...
PMID:[Studies on the induction of transplantation tolerance and immune reconstitution through combined strategies]. 1794 May 78

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.
 ...
PMID:Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation. 1831 70

Decreased severity of graft-versus-host disease after mismatched umbilical cord blood (UCB) transplantation may be attributed in part to the increased propensity to apoptosis of UCB T cells following activation. Interleukin (IL)-15, a pleiotropic cytokine that is essential for T-cell proliferation and survival, may serve as promising immunomodulative therapy post-CB transplantation for its anti-apoptotic effect. This study aimed to determine the kinetics of Fas or tumor necrosis factor-alpha receptor (TNFR) mediated caspase-3 expression and apoptosis of anti-CD3/anti-CD28 activated UCB T cells in the influence of IL-15. Activated caspase-3 expression was analyzed by Western blotting and the percentage of apoptotic cells was determined by annexin-V/propidium iodide (PI) flow cytometric staining. Significant expression of Fas and TNFR2 was detected on anti-CD3/anti-CD28 pre-activated UCB T cells. These cells were susceptible to anti-Fas but not TNF-alpha-induced apoptosis. Kinetic study shows that caspase-3 expression became evident at 6th-8th h following anti-Fas stimulation, while early apoptotic cells with annexin-V(+)/PI(-) expression appeared at 12th-16th h. IL-15, though successful in decreasing apoptosis in pre-activated UCB T cells, failed to completely prevent Fas-mediated caspase-3 expression and apoptosis of CB T cells. The pre-activated UCB and adult peripheral blood T cells behaved similarly with regard to death receptor expression, caspase-3 expression and apoptosis upon Fas-engagement. Although IL-15 promotes overall activated UCB T-cell survival, it did not particularly prevent Fas-mediated activation-induced cell death.
 ...
PMID:Susceptibility to Fas and tumor necrosis factor-alpha receptor mediated apoptosis of anti-CD3/anti-CD28-activated umbilical cord blood T cells. 1871 15

Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X(L) expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4(+) and CD8(+) T cells. Transplantation of RAG-2-eGFP-transgenic BM revealed that proliferating eGFP(lo)CD44(hi) donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFP(hi)CD44(lo) recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester-labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44(hi) phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells.
 ...
PMID:Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation. 1881 89

Alloreactive donor cytolytic T lymphocytes play a critical role in pathophysiology of acute graft-versus-host disease (GVHD). As GVHD progression involves tumor necrosis factor superfamily receptor activation, and as apoptotic signaling for some tumor necrosis factor superfamily receptors might involve acid sphingomyelinase (ASMase)-mediated ceramide generation, we hypothesized that ASMase deletion would ameliorate GVHD. Using clinically relevant mouse models of acute GVHD in which allogeneic bone marrow and T cells were transplanted into asmase+/+ and asmase(-/-) hosts, we identify host ASMase as critical for full-blown GVHD. Lack of host ASMase reduced the acute inflammatory phase of GVHD, attenuating cytokine storm, CD8+ T-cell proliferation/activation, and apoptosis of relevant graft-versus-host target cells (hepatocytes, intestinal, and skin cells). Organ injury was diminished in asmase(-/-) hosts, and morbidity and mortality improved at 90 days after transplantation. Resistance to cytolytic T lymphocyte-induced apoptosis was found at the target cell membrane if hepatocytes lack ASMase, as hepatocyte apoptosis required target cell ceramide generation for formation of ceramide-rich macrodomains, sites concentrating proapoptotic Fas. These studies indicate a requirement for target cell ASMase in evolution of GVHD in liver, small intestines, and skin and provide potential new targets for disease management.
 ...
PMID:Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease. 2007 75

Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.
 ...
PMID:The allogeneic graft-versus-cancer effect. 1973 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>