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)

A major goal of the transplant field is to tolerize donor T cells to prevent graft-versus-host disease (GVHD) (1). We describe an ex vivo approach in which the blockade of CD40 ligand (CD40L:CD154):CD40 interactions, a pathway required for optimal T cell expansion, induces donor CD4(+) T cells to become tolerant to host alloantigens (2). High doses of tolerized cells did not cause GVHD lethality in vivo. T cells had intact responses to antigens not present during tolerization. Tolerance was long lived and not readily reversible in vivo. These data have significant implications for the use of tolerization approaches to prevent human GVHD.
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PMID:CD4(+) T cells tolerized ex vivo to host alloantigen by anti-CD40 ligand (CD40L:CD154) antibody lose their graft-versus-host disease lethality capacity but retain nominal antigen responses. 969 Oct 83

Posttransplant infection associated with host immune deficiency is the major cause of nonrelapse mortality of human bone marrow transplant recipients. In a new murine model of posttransplant infection, allogeneic bone marrow transplant recipients were infected with herpes simplex virus-1 (HSV-1) via intraperitoneal inoculation 12 weeks after transplantation. Allogeneic transplant recipients with graft-versus-host disease (GVHD) had significantly increased mortality from HSV-1 encephalitis, with deficiencies of both specific anti-HSV-1 antibody and total serum IgG2a. GVHD mice displayed a Th2 cytokine profile (increased interleukin-4 [IL-4] and decreased interferon-gamma) and decreased lipopolysaccharide (LPS) responses, suggesting that both T-cell and B-cell defects contributed to the impaired production of antibody. Because passive transfer of hyperimmune serum protected mice from HSV-1 infection, we hypothesized that CD40 ligand (CD40L), which induces B-cell maturation, would protect mice from HSV-1 infection. CD40L-treated GVHD mice showed elevated IgG2a levels and increased survival compared with vehicle-treated transplant recipients.
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PMID:Recombinant CD40L treatment protects allogeneic murine bone marrow transplant recipients from death caused by herpes simplex virus-1 infection. 983 55

We report a case of an 11-year-old boy who underwent successful bone marrow transplantation for X-linked hyper-IgM syndrome (XHIM). The donor was an HLA-matched brother. The patient was conditioned with busulfan, cyclophosphamide and anti-thymocyte globulin. He received 4.7 x 10(8) marrow cells per kg from the donor. Prophylaxis against graft-versus-host disease consisted of cyclosporine and short-term methotrexate. The clinical course after the bone marrow transplantation was uneventful, and 12 months after transplantation the patient was doing well with no need for therapy. We examined expression of the CD40 ligand (CD40L) on the patient's activated T lymphocytes and in vitro production of immunoglobulins by his lymphocytes. Although expression of CD40L was totally absent before the bone marrow transplant, subnormal expression appeared after the transplantation. In vitro production of IgG and IgA also was improved by the transplant. Based on our experience bone marrow transplantation appears to be a reasonable therapeutic option for patients with XHIM if HLA-matched family donors are available.
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PMID:Successful bone marrow transplantation in a child with X-linked hyper-IgM syndrome. 1037 76

Induction of an optimal immune response will likely be a prerequisite for successful immunotherapy of human leukemias and other malignancies. Dendritic cells are highly effective at inducing an immune response to antigens to which the host is unresponsive, while transgenic expression of the costimulator molecule CD40 ligand (gp39/CD154) and the T cell growth factor interleukin 2 (IL2) are also able to augment immune responsiveness. We therefore investigated whether a combination of these two distinctive approaches to immunostimulation could safely increase the anti-tumor immune response compared to each stimulus alone. We injected BALB/CBYJ mice with syngeneic dendritic cells (DC) exposed to A20 lymphoblastic leukemia cell-derived peptides and proteins which had been acid-eluted from the cell surface. In additional mice, the pulsed DC were mixed with genetically modified syngeneic fibroblasts that were expressing CD40 ligand or secreting interleukin 2 (IL2). Three days after their third, weekly, vaccination, they were challenged with parental A20 cells. Tumor growth was suppressed by responses to pulsed DC alone (P < 0.02). This suppression was further enhanced when pulsed DC were coinjected with fibroblasts expressing CD40 ligand and IL2 (P < 0.0005 compared to DC alone) even though CD40 ligand and IL2-expressing fibroblasts alone offered no significant protection in this model. Mice receiving the full complement of immunostimulants either failed to develop visible tumors or developed small tumors which quickly necrosed and regressed, allowing the mice to become long term tumor-free survivors. Antibody mediated depletion of either CD4+ or CD8+ T-cell subset significantly reduced the level of protection afforded by the vaccination. However, it became evident that this intensive stimulation of the immune system lead not only to tumor eradication but also to destruction of cells bearing normal self antigens. Hence, 60 days after challenge with A20 cells all mice in the DC/IL2/CD40 ligand group developed a severe, systemic autoimmune disorder that resembled graft versus host disease and manifest itself by significant peripheral blood cytotoxicity against autologous fibroblasts, blood dyscrasias, gross hepatosplenomegaly, cachexia and fur loss. This phenomenon depended on CD8+ cytotoxic T lymphocytes. Our results therefore suggest that the most effective strategies of immunotherapy against leukemia may also exceed the threshold of anergic cells, leading to a loss of self tolerance to normal self-antigens and the induction of an CD8+ anti-self effector response.
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PMID:Autoimmune disease induced by dendritic cell immunization against leukemia. 1037 48

The optimal approach for stem cell transplantation in children with immunodeficiency has yet to be determined. Conditioning therapy is necessary for reliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short- and long-term treatment-related toxicity. Whether bone marrow transplantation with a nonmyeloablative preparative regimen was sufficient for the establishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated. Eight patients with severe immunodeficiency states underwent T-cell replete bone marrow transplantation from a human leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine-melphalan-anti-lymphocyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. All patients were engrafted with predominantly donor hematopoiesis, and the duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed chimerism. At a median follow-up of 1 year, all patients have had good recovery of CD3(+) T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation indices. The rate of immune reconstitution is comparable with that of historical controls undergoing standard myeloablative protocols. Two patients with CD40 ligand deficiency now show significant expression, and a patient with adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative stem cell transplantation permits rapid engraftment from both sibling and unrelated donors with minimal toxicity even in the presence of severe organ dysfunction. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer significant advantages compared with standard protocols by combining adequate immune reconstitution with reduced short- and long-term toxicity. (Blood. 2000;96:1239-1246)
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PMID:Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. 1094 63

We have previously shown that the keys to high-level nontoxic chimerism in syngeneic models are stem cell toxic, nonmyelotoxic host treatment as provided by 100-cGy whole-body irradiation and relatively high levels of marrow stem cells. This approach was unsuccessful in H-2 mismatched B6.SJL to BALB/c marrow transplants, but with tolerization, stable multilineage chimerism was obtained. Ten million B6.SJL spleen cells were infused intravenously into BALB/c hosts on day -10 and (MR-1) anti-CD40 ligand monoclonal antibody (mAb) injected intraperitoneally at varying levels on days -10, -7, -3, 0, and +3 and the BALB/c mice irradiated (100 cGy) and infused with 40 million B6.SJL/H-2 mismatched marrow cells on day 0. Stable multilineage chimerism at levels between 30% to 40% was achieved in the great majority of mice at 1.6 mg anti-CD40 ligand mAb per injection out to 64 weeks after transplantation, without graft-versus-host disease. The transplanted mice were also tolerant of donor B6.SJL, but not third-party CBA/J skin grafts at 8 to 9 and 39 to 43 weeks after marrow transplantation. These data provide a unique model for obtaining stable partial chimerism in H-2 mismatched mice, which can be applied to various clinical diseases of man such as sickle cell anemia, thalassemia, and autoimmune disorders.
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PMID:Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice. 1115 37

Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTbetaR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.
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PMID:Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. 1185 28

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
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PMID:Novel therapeutics for the treatment of graft-versus-host disease. 1222 48

Long-term multilineage allochimerism can be obtained in H2-mismatched B6.SJL to BALB/c transplants with host irradiation of 100 cGy, donor spleen cell pre-exposure and costimulator blockade with anti-CD40 ligand (CD40L) antibody. We evaluated this allochimerism approach in murine marrow transplants with different degrees of major histocompatibility complexe (MHC) mismatching; these include: (1) H2-mismatched transplant H2Kk to H2Kb, (2) full haplo-identical transplant H2Kbd to H2Kbk, (3) a partial haplo-identical transplant H2Kd to H2Kbd and (4) an MHC class II mismatch. Levels of chimerism increased up to 12 weeks and then stayed relatively stable up to 1 year after transplant. At 18 weeks post-transplant, the H2-mismatched, haplo-identical, partial haplo-identical and class II-mismatch transplants evidenced 17.9+/-4.4, 40.7+/-0.9, 25.1+/-4.19 and 33.7+/-3.5% donor chimerism, respectively. Dropping the anti-CD40 antibody treatment and spleen cells or changing the schedule of antibody to one injection, in haplo-identical or full-mismatched transplants resulted in no donor-derived chimerism. On the other hand, these still resulted in minor chimerism in class II-mismatched transplants. Lineage analysis of peripheral blood at 6 and 12 months post-transplant demonstrated a significant shift toward increased chimeric lymphocytes and decreased chimeric granulocytes in the full H2 as compared with haplo-identical or class II transplants. Transplantation with anti-CD40L antibody eliminated both graft-versus-leukemia and graft-versus-host disease (GVHD) and delayed lymphocyte infusion did not rescue animals from fatal leukemia. In conclusion, under the conditions of our tolerization regimen, a haplo transplant gives higher engraftment levels than a full H2 mismatch, and despite lower engraftment levels, a class II-mismatched transplant can be successfully accomplished with only 100 cGy and no CD40L blockade.
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PMID:Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity. 1297 Jul 89

CD40 ligand (CD40L) deficiency causes recurrent sinopulmonary infection, Pneumocystis carinii pneumonia, and Cryptosporidium parvum infection. Approximately 40% to 50% of patients survive to the third decade: long-term survival is unclear. Hematopoietic stem cell transplantation (HSCT) is curative. We present a retrospective analysis of 38 European patients undergoing HSCT for CD40L deficiency in 8 European countries between 1993 and 2002. Donor stem cell source included 14 HLA-identical siblings, 22 unrelated donors, and 2 phenotypically matched parental stem cells (12 T-cell depleted). Of the patients, 34 engrafted and 26 (68%) survived; 3 had autologous reconstitution, 22 (58%) were cured, and 1 engrafted but has poor T-cell immune reconstitution. There were 18 evaluated patients who responded to vaccination. Of the patients, 12 (32%) died from infection-related complications, with severe cryptosporidiosis in 6. Grades 2 to 4 graft-versus-host disease (GvHD) associated with infection occurred in 6 of 12 fatal cases. HSCT cured 58% of patients, 72% of those without hepatic disease. Early T-cell function following whole marrow HSCT may limit cryptosporidial disease, but survival was similar after T-cell-depleted HSCT. Preexisting lung damage was the most important adverse risk factor. Further studies will determine optimal timing and type of HSCT.
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PMID:Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002. 1452 61


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